Endovascular stents for abdominal aortic aneurysms: a systematic ...

Health Technology Assessment 2009; Vol. 13: No. 48Endovascular stents for abdominal aorticaneurysms: a systematic review andeconomic modelD Chambers, D Epstein, S Walker,D Fayter, F Paton, K Wright,J Michaels, S Thomas, M Sculpher andN WoolacottOctober 2009DOI: 10.3310/hta13480Health Technology AssessmentNIHR HTA programmewww.hta.ac.uk

HTAHow to obtain copies of this and other HTA programme reportsAn electronic version of this publication, in Adobe Acrobat format, is available for downloading free ofcharge for personal use from the HTA website (www.hta.ac.uk). A fully searchable CD-ROM is alsoavailable (see below).Printed copies of HTA monographs cost £20 each (post and packing free in the UK) to both public andprivate sector purchasers from our Despatch Agents.Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is£2 per monograph and for the rest of the world £3 per monograph.You can order HTA monographs from our Despatch Agents:– fax (with credit card or official purchase order)– post (with credit card or official purchase order or cheque)– phone during office hours (credit card only).Additionally the HTA website allows you either to pay securely by credit card or to print out yourorder and then post or fax it.Contact details are as follows:HTA DespatchEmail: orders@hta.ac.ukc/o Direct Mail Works Ltd Tel: 02392 492 0004 Oakwood Business Centre Fax: 02392 478 555Downley, HAVANT PO9 2NP, UK Fax from outside the UK: +44 2392 478 555NHS libraries can subscribe free of charge. Public libraries can subscribe at a very reduced cost of£100 for each volume (normally comprising 30–40 titles). The commercial subscription rate is £300per volume. Please see our website for details. Subscriptions can be purchased only for the current orforthcoming volume.Payment methodsPaying by chequeIf you pay by cheque, the cheque must be in pounds sterling, made payable to Direct Mail Works Ltdand drawn on a bank with a UK address.Paying by credit cardThe following cards are accepted by phone, fax, post or via the website ordering pages: Delta, Eurocard,Mastercard, Solo, Switch and Visa. We advise against sending credit card details in a plain email.Paying by official purchase orderYou can post or fax these, but they must be from public bodies (i.e. NHS or universities) within the UK.We cannot at present accept purchase orders from commercial companies or from outside the UK.How do I get a copy of HTA on CD?Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact Direct Mail Works (seecontact details above) by email, post, fax or phone. HTA on CD is currently free of charge worldwide.The website also provides information about the HTA programme and lists the membership of the variouscommittees.

Endovascular stents for abdominal aorticaneurysms: a systematic review andeconomic modelD Chambers, 1 * D Epstein, 2 S Walker, 2D Fayter, 1 F Paton, 1 K Wright, 1J Michaels, 3 S Thomas, 3 M Sculpher 2 andN Woolacott 11Centre for Reviews and Dissemination, University of York, UK2Centre for Health Economics, University of York, UK3Academic Vascular Unit, University of Sheffield, Northern General Hospital,Sheffield, UK*Corresponding authorDeclared competing interests of authors: Three of the authors (David Epstein,Jonathan Michaels and Mark Sculpher) have undertaken and published previous work on theeffectiveness and cost-effectiveness of EVAR devices funded by the NIHR Health TechnologyAssessment programme. Also, Mark Sculpher has undertaken consultancy work forMedtronic in the past in clinical areas unrelated to vascular disease or EVAR.Published October 2009DOI: 10.3310/hta13480This report should be referenced as follows:Chambers D, Epstein D, Walker S, Fayter D, Paton F, Wright K, et al. Endovascular stents forabdominal aortic aneurysms: a systematic review and economic model. Health Technol Assess2009;13(48).Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, ExcerptaMedica/EMBASE and Science Citation Index Expanded (SciSearch ® ) and Current Contents ® /Clinical Medicine.

NIHR Health Technology Assessment programmeThe Health Technology Assessment (HTA) programme, part of the National Institute for HealthResearch (NIHR), was set up in 1993. It produces high-quality research information on theeffectiveness, costs and broader impact of health technologies for those who use, manage and provide carein the NHS. ‘Health technologies’ are broadly defined as all interventions used to promote health, preventand treat disease, and improve rehabilitation and long-term care.The research findings from the HTA programme directly influence decision-making bodies such as theNational Institute for Health and Clinical Excellence (NICE) and the National Screening Committee(NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that theyform a key component of the ‘National Knowledge Service’.The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are threeroutes to the start of projects.First is the commissioned route. Suggestions for research are actively sought from people working in theNHS, from the public and consumer groups and from professional bodies such as royal colleges and NHStrusts. These suggestions are carefully prioritised by panels of independent experts (including NHS serviceusers). The HTA programme then commissions the research by competitive tender.Second, the HTA programme provides grants for clinical trials for researchers who identify researchquestions. These are assessed for importance to patients and the NHS, and scientific rigour.Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programmecommissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring togetherevidence on the value of specific technologies.Some HTA research projects, including TARs, may take only months, others need several years. Theycan cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence,undertaking a trial, or other research collecting new data to answer a research problem.The final reports from HTA projects are peer reviewed by a number of independent expert referees beforepublication in the widely read journal series Health Technology Assessment.Criteria for inclusion in the HTA journal seriesReports are published in the HTA journal series if (1) they have resulted from work for the HTAprogramme, and (2) they are of a sufficiently high scientific quality as assessed by the referees andeditors.Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisaland synthesis methods (to minimise biases and random errors) would, in theory, permit the replicationof the review by others.The research reported in this issue of the journal was commissioned and funded by the HTA programmeon behalf of NICE as project number 07/09/01. The protocol was agreed in August 2007. The assessmentreport began editorial review in April 2008 and was accepted for publication in February 2009. Theauthors have been wholly responsible for all data collection, analysis and interpretation, and for writingup their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report andwould like to thank the referees for their constructive comments on the draft document. However, they donot accept liability for damages or losses arising from material published in this report.The views expressed in this publication are those of the authors and not necessarily those of the HTAprogramme or the Department of Health.Editor-in-Chief:Series Editors:Professor Tom Walley CBEDr Aileen Clarke, Professor Chris Hyde, Dr John Powell,.Dr Rob Riemsma and Professor Ken SteinISSN 1366-5278© 2009 Queen’s Printer and Controller of HMSOThis monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals providedthat suitable acknowledgement is made and the reproduction is not associated with any form of advertising.Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University ofSouthampton Science Park, Southampton SO16 7NS, UK.Published by Prepress Projects Ltd, Perth, Scotland (www.prepress-projects.co.uk), on behalf of NETSCC, HTA.Printed on acid-free paper in the UK by the Charlesworth Group.T

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48AbstractEndovascular stents for abdominal aortic aneurysms:a systematic review and economic modelD Chambers, 1* D Epstein, 2 S Walker, 2 D Fayter, 1 F Paton, 1 K Wright, 1J Michaels, 3 S Thomas, 3 M Sculpher 2 and N Woolacott 11Centre for Reviews and Dissemination, University of York, UK2Centre for Health Economics, University of York, UK3Academic Vascular Unit, University of Sheffield, Northern General Hospital, Sheffield, UK*Corresponding authorObjective: To determine the clinical effectiveness andcost-effectiveness of endovascular aneurysm repair(EVAR) of infrarenal abdominal aortic aneurysms (AAAs)in patients at varying levels of risk.Data sources: The following bibliographic databaseswere searched (2005–February 2007): BIOSISPreviews, ® CINAHL, Cochrane Central Register ofControlled Trials, EMBASE, ISI Proceedings, MEDLINE, ®MEDLINE ® In-Process & Other Non-Indexed Citations,Science Citation Index and Zetoc Conferences.Review methods: A systematic review of the clinicaleffectiveness of EVAR was performed using standardmethods. Meta-analysis was employed to estimatea summary measure of treatment effect on relevantoutcomes based on intention to treat analyses. A secondsystematic review was undertaken to identify existingcost-effectiveness analyses of EVAR compared withopen surgery and non-surgical interventions. Two newdecision models were developed to inform the review.Results: Six RCTs were included in the clinicaleffectiveness review. Thirty-four studies evaluated therole of patients’ baseline characteristics in predictingrisks of particular outcomes after EVAR. The majoritywere based on data relating to devices in currentuse from the EUROSTAR registry. Compared withopen repair EVAR reduces operative mortality (oddsratio 0.35, 95% CI 0.19 to 0.63) and medium-termaneurysm-related mortality (hazard ratio 0.49, 95%CI 0.29 to 0.83) but offers no significant difference inall-cause mortality. EVAR is associated with increasedrates of complications and reinterventions, which arenot offset by any increase in health-related quality oflife. EVAR trial 2 comparing EVAR with non-surgicalmanagement in patients unfit for open repair foundno differences in mortality between groups; however,substantial numbers of patients randomised to nonsurgicalmanagement crossed over to receive surgicalrepair of their aneurysm. The cost-effectivenesssystematic review identified six published decisionmodels. Both models considered relevant for thedecision in the UK concluded that EVAR was not costeffectiveon average compared with open repair ata threshold of £20,000 per quality-adjusted life-year(QALY). Another model concluded that EVAR wouldbe on average more cost-effective than no surgicalintervention in unfit patients at this threshold. TheMedtronic model concluded that EVAR was morecost-effective than open repair for fit patients at thisthreshold. The York economic evaluations found thatEVAR is not cost-effective compared with open repairon average at a threshold of £30,000 per QALY, withthe results very sensitive to model assumptions and thebaseline risk of operative mortality. Exploratory analysisto evaluate management options in patients unsuitablefor open surgery suggested that the cost-effectivenessof EVAR may be sensitive to aneurysm size and patient’sage at operation. Indicative modelling suggests thatEVAR may be cost-effective for small aneurysms insome patient groups. Ongoing RCTs will provide furtherevidence relating to these patients.Conclusion: Open repair is more likely to be costeffectivethan EVAR on average in patients consideredfit for open surgery. EVAR is likely to be more costeffectivethan open repair for a subgroup of patientsat higher risk of operative mortality. These results arebased on extrapolation of mid-term results of clinicaltrials. Evidence does not currently support EVAR forthe treatment of ruptured aneurysms. Further followupof the existing UK trials should be undertaken andthe relative costs of procedures and devices should beinvestigated further.iii© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48ContentsGlossary and list of abbreviations .............. viiExecutive summary .................................... xiii1 Background ................................................ 1Description of health problem ................... 1Current service provision ........................... 1Description of technology under .assessment .............................................. 2Risk score measures for surgical risk .......... 32 Definition of decision problem .................. 7Decision problem ....................................... 7Overall aims and objectives of assessment . 7Confidential information ........................... 73 Assessment of clinical effectiveness ........... 9Methods for reviewing clinical .effectiveness ........................................... 9Results of the review of clinical .effectiveness ........................................... 11Discussion of assessment of clinicaleffectiveness ........................................... 714 Assessment of cost-effectivenessevidence ..................................................... 77Systematic review of existing cost-effectivenessevidence ................................................. 77York economic assessment ......................... 995 Assessment of factors relevant to theNHS and other parties .............................. 1376 Discussion ................................................... 139Statement of principal findings ................. 139Strengths and limitations of the .assessment .............................................. 139Uncertainties .............................................. 1417 Conclusions ................................................ 143Implications for service provision .............. 143Suggested research priorities ..................... 143Acknowledgements .................................... 145References .................................................. 147Appendix 1 Literature search strategies .... 163Appendix 2 Quality assessment ................. 171Appendix 3 Survey of health-care resourceuse after EVAR and open repair ................. 187Appendix 6 Characteristics of the averageUK population .......................................... 189Health Technology Assessment reportspublished to date ....................................... 191Health Technology Assessmentprogramme ................................................ 211Appendix 4 Data extraction tables ............ 215Appendix 5 Table of excluded studies withrationale ..................................................... 315*Due to the extensive nature of the appendices, these are available only in electronic format. The PDF fileof the full report is available at www.hta.ac.uk/1678. It will also be available on HTA on CD (see the insidefront cover for full details).v© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48GlossaryGlossary and list of abbreviationsAdverse effects and complications Includesaneurysm-related outcomes such as ruptureand events specific to endovascular repair,major morbidity (e.g. cardiac events) andreintervention including conversion fromendovascular repair to open procedure andsecondary intervention.Aneurysm-related mortality Death fromaneurysm-related causes such as rupture. Itincludes operative mortality and can, but doesnot always, include postoperative mortality.Chi-squared (χ 2 ) test A statistical test usedto assess heterogeneity by testing the nullhypothesis that the true treatment effects are thesame in each study.Comorbidity The presence of one or moredisorders (or diseases) in addition to a primarydisease or disorder.Complications See adverse effects andcomplications.Confidence interval (CI) The range ofuncertainty about an estimate of a treatmenteffect. It is the range of values above and belowthe point estimate that is likely to include thetrue value of the treatment effect. The 95% CIindicates that there is a 95% probability that theCI calculated from a particular study includesthe true value of a treatment effect.Cost-effectiveness acceptability curve Agraphical representation of the probability of anintervention being cost-effective over a rangeof monetary values for the health system’s costeffectivenessthreshold.Cost-effectiveness analysis The estimationof the costs and health benefits of mutuallyexclusive treatment strategies in which theconsequences are measured in natural units suchas years of life gained.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.Cox proportional hazards analysis Analysis ofone or more risk factors over time on an endpoint such as death.Device migration Migration can occur postimplantation when there is any movement ordisplacement of the stent graft in relation tothe native aorta or renal arteries. The risk ofmigration increases with time and can resultin the loss of device fixation. To maximiseiliac fixation length, the stent graft is placed atthe origin of the hypogastric arteries. Devicemigration may not require further treatment andcan be monitored or it can result in aneurysmrupture or endoleak, requiring secondaryintervention.Disutility The reduction in health-relatedquality of life (measured using utilities)compared with a reference such as the generalpopulation.Endoleak Persistence of blood flow outside theendovascular stent graft but within the aneurysmsac or adjacent vessels in which the graft isdeployed. Type I is perigraft or graft related(proximal anastomosis, distal anastomosis,occluder). Blood flow into the aneurysmsac occurs because of an incomplete seal orineffective seal at the end of the graft. This typeof endoleak usually occurs in the early courseof treatment, but may also occur later. Type IIis retrograde or collateral (mesenteric, lumbar,renal accessory). Blood flow into the aneurysmsac occurs because of opposing blood flow fromcollateral vessels. In some circumstances, whenthere are two or more patent vessels, a situationof inflow and outflow develops creating an activeblood flow within the channel created within theaneurysm sac. Type III occurs midgraft (fabrictear, graft dislocation, graft disintegration).Blood flow into the aneurysm sac occursbecause of inadequate or ineffective sealing ofoverlapping graft joints or rupture of the graftfabric. Again, this endoleak usually occurs earlycontinuedvii

Glossary and list of abbreviationsafter treatment, because of technical problems,or later, because of device breakdown. Type IVis due to the porosity of the graft fabric, causingblood to pass through from the graft and intothe aneurysm sac.Endovascular repair A technique that involvesplacing a stent graft prosthesis at the site of theaneurysm. The stent graft is inserted through asmall incision in the femoral artery in the groinand then carried to the site of the aneurysmusing catheters and guidewires and placed inposition under radiographic guidance.EUROSTAR registry A multicentre Europeandatabase of the outcome of endovascular repairof infrarenal aortic aneurysms.Fixed-effects model A statistical modelthat assumes only within-study variation asinfluencing the uncertainty of results (as reflectedin the confidence interval) of a meta-analysis.Variation between the estimates of effect fromeach study (heterogeneity) does not affect theconfidence interval in a fixed-effects model.Hazard ratio The degree of increased ordecreased risk of death or other clinical outcomeover a period of time.Heterogeneity The differences/variabilitybetween the individual studies in the estimates ofeffects.Homogeneity The degree to which the results ofstudies are similar.I 2 statistic A measure to estimate how muchof the total variation between the treatmentestimates can be attributed to statisticalheterogeneity rather than chance. It gives theproportion of the total variation that is due toheterogeneity between study results.Infrarenal abdominal aorticaneurysm Weakening of the wall of theaorta can lead to a dilatation of the vessel, oraneurysm, in the lower infrarenal part of theabdominal aorta.Kaplan–Meier survival analysis A method ofanalysis that enables calculation of survival timefor any given proportion of the sample, theprobability of survival and the comparison ofthe difference in proportions surviving in twogroups.Karnofsky functional autonomy score Allowspatients to be classified according to theirfunctional impairment. This can be used tocompare the effectiveness of different therapiesand to assess the prognosis in individual patients.The lower the Karnofsky score, the worse thesurvival for most serious illnesses.Meta-analysis A method of combining studiesto produce an overall summary of the treatmenteffect across studies (see also fixed-effects modeland random-effects model).Multiple regression A method for estimatingthe relationship between a dependent variablesuch as mortality (i.e. outcome) and more thanone independent explanatory variable such asage or gender. Also referred to as multivariableregression.Multivariate analysis Method for estimatingjointly the relationship between severaldependent variables (outcomes) and severalindependent explanatory variables.Neck angulation Significant aortic neckangulation may predispose to suboptimaloutcome after endovascular abdominal aorticaneurysm repair. Defined as severe (≥ 60°),moderate (40–59°) and mild (< 40°) aortic neckangulation between the infrarenal aortic neckand the longitudinal axis of the aneurysm.Odds ratio A way of comparing whether theodds, or likelihood, of a certain event is the samefor two groups; the odds refers to the ratio ofthe number of people having an event to thenumber not having an event.Perioperative Generally refers to the threephases of surgery – preoperative, intraoperativeand postoperative – and includes, for example,ward admission, anaesthesia, surgery andrecovery.Quality of life (health-related quality of life) Aconcept incorporating all of the factors thatmight impact on an individual’s life, includingfactors such as the absence of disease or infirmityas well as other factors that might affect theirphysical, mental and social well-being.viii

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Quality-adjusted life-year (QALY) Indexof health gain in which survival duration isweighted or adjusted by the patient’s (healthrelated)quality of life during the survival period.QALYs have the advantage of incorporatingchanges in both quantity (mortality) and quality(morbidity) of life.Random-effects model A statistical modelsometimes used in meta-analysis in whichboth within-study sampling error (variance)and between-study variation are included inthe assessment of the uncertainty (confidenceinterval) of the results of a meta-analysis.Reintervention See adverse effects andcomplications.Sensitivity analysis A mathematical methodthat examines uncertainty associated withparameters estimated in the analysis to testthe robustness of the analysis findings. Inone-way sensitivity analysis each parameter isvaried individually; in multiway analysis two ormore parameters are varied at the same time;threshold analysis identifies the critical valuesabove or below which the results of a study vary;and analysis of extremes is used to examinethe most pessimistic and the most optimisticscenarios. Finally, probabilistic sensitivity analysisattributes distributions of probabilities touncertain variables that are incorporated withina model.Short Form-36 (SF-36) The SF-36 is amultipurpose, short-form health survey. Itproduces an 8-scale profile of functional healthand well-being scores as well as psychometricallybased physical and mental health summarymeasures and a preference-based health utilityindex. It is a generic measure as opposed to onethat targets a specific age, disease or treatmentgroup.Society for Vascular Surgery/InternationalSociety for Cardiovascular Surgery (SVS/ISCVS) model Risk stratification model thatincludes three levels of risk: level I [age 75–85years; stable angina with mild angiographiccoronary artery disease (CAD) or normalperfusion scan; ejection fraction 30–50%;chronic obstructive pulmonary disease (COPD)with normal activities of daily living; serumcreatinine < 2 mg/dl; estimated mortality fromopen surgical repair 3–5%]; level II (age 85–90years; stable angina with moderate angiographicCAD or mild to moderate abnormal perfusionscan; ejection fraction 20–30%; COPD withmoderate to severe pulmonary dysfunction;serum creatinine 2–3.5 mg/dl; estimatedmortality 6–8%); level III (age > 90 years; classII–III angina with significant myocardium at riskbased on coronary angiography or perfusionscan; ejection fraction < 20%; COPD requiringhome oxygen; serum creatinine > 3.5 mg/dl oron chronic dialysis; estimated mortality 8–13%).Utility A measure of the strength of anindividual’s preference for a given health stateor outcome. Utilities assign numerical valueson a scale from 0 (death) to 1 (optimal or‘perfect’ health), and provide a single numberthat summarises health-related quality of life.Negative values of utility are feasible.Weibull model A specific parametric survivalfunction modelling the relationship between therate of an event (e.g. death) and time.ix© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Glossary and list of abbreviationsList of abbreviationsAAAASACAD/MICAESARCCICECHFCICiCCINAHLCOPDCPICTDAREEQ-5DEVARGASHRHRQoLHTAICERIQRITTMASSabdominal aortic aneurysmAmerican Society ofAnesthesiologistscoronary artery (heart) disease/myocardial infarctionComparison of SurveillanceVersus Aortic Endografting forSmall Aneurysm Repair trialCharlson Comorbidity IndexConformité Européennecongestive heart failureconfidence intervalcommercial-in-confidenceCumulative Index to Nursingand Allied Health Literaturechronic obstructive pulmonarydiseaseCustomized Probability Indexcomputed tomographyDatabase of Abstract of Reviewsof EffectsEuroQoL 5 dimensionsendovascular aneurysm repairGlasgow Aneurysm Scorehazard ratiohealth-related quality of lifeHealth Technology Assessmentincremental cost-effectivenessratiointerquartile rangeintention to treatMulticentre AneurysmScreening StudyMeSHMRCMRINExT ERANICENLHNVDOROVERQALYQoLRCTRETAROCSDSESF-36SVS/ISCVSTRIPUKSATMedical Subject Headings in theMEDLINE thesaurusMedical Research Councilmagnetic resonance imagingNational Expertise Based Trialof Elective Repair of AbdominalAortic AneurysmsNational Institute for Healthand Clinical ExcellenceNational Library for HealthNational Vascular Database(currently covering open repairof aneurysms)odds ratioOpen Surgery VersusEndovascular Repair trialquality-adjusted life-yearquality of liferandomised controlled trialRegistry of EndovascularTreatment of Abdominal AorticAneurysmsreceiver operating characteristicstandard deviationstandard errorShort Form-36Society for Vascular Surgery/International Society forCardiovascular SurgeryTurning Research Into PracticeUK Small Aneurysm TrialAll abbreviations that have been used in this report are listed here unless the abbreviation is wellknown (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only infigures/tables/appendices, in which case the abbreviation is defined in the figure legend or in thenotes at the end of the table.x

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48NoteThis monograph is based on the TechnologyAssessment Report produced for NICE. Thefull report contained a considerable amount ofinformation that was deemed commercial-inconfidenceor academic-in-confidence. The fullreport was used by the Appraisal Committeeat NICE in their deliberations. The full reportwith each piece of commercial-in-confidence oracademic-in-confidence information removedand replaced by the statement ‘commercial-inconfidenceinformation removed’ or ‘academic-inconfidenceinformation removed’ is available onthe NICE website (www.nice.org.uk).The present monograph presents as full aversion of the report as is possible while retainingreadability, but some sections, sentences, tablesand figures have been removed. Readers shouldbear in mind that the discussion, conclusions andimplications for practice and research are based onall the data considered in the original full NICEreport.xi© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Executive summaryBackgroundAbdominal aortic aneurysms (AAAs) carry a highrisk of rupture, which is associated with a mortalityrate of about 80%. AAAs can be treated by surgicalrepair to prevent rupture. However, open repairinvolves significant risks and approximately 25%of patients with an AAA requiring surgery areconsidered unfit for open surgery. Endovascularaneurysm repair (EVAR) is a minimally invasivetechnique that has been used to treat patientswith appropriate aneurysm morphology who areclassified as either fit for open repair or unfit.EVAR is used both as an elective procedure and totreat symptomatic and ruptured aneurysms.ObjectiveThe management options available after diagnosisof AAA can be classified as immediate electivesurgery with open repair; immediate electivesurgery with EVAR; surveillance with an optionto defer surgery; or a decision to rule out surgeryentirely. The objective of this assessment is todetermine the clinical effectiveness and costeffectivenessof EVAR for repair of infrarenal AAAsin patients at varying levels of risk, including thosewho are appropriate for open repair and those whoare not.MethodsA systematic review of the clinical effectiveness ofEVAR was performed. Recent systematic reviewswere used to identify randomised controlled trials(RCTs) and other clinical studies. Additionalsearches (2005–February 2008) were conductedto search for recent RCTs, publications relatingto named registries [Registry of EndovascularTreatment of Abdominal Aortic Aneurysms (RETA)and the European Collaborators on Stent–GraftTechniques for Abdominal Aortic Aneurysm Repair(EUROSTAR) for EVAR, and the National VascularDatabase (NVD) for open surgery] and studieson the relationship between patients’ baselinerisks and outcomes. The following bibliographicdatabases were searched: BIOSIS Previews, ®© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.Cumulative Index to Nursing and Allied HealthLiterature (CINAHL), Cochrane Central Registerof Controlled Trials, EMBASE, ISI Proceedings,MEDLINE, ® MEDLINE ® In-Process & Other Non-Indexed Citations, Science Citation Index andZetoc Conferences. Searches were not restricted bylanguage or study design and studies written in anylanguage were eligible for inclusion in the review.Studies of EVAR in patients with asymptomaticor symptomatic and ruptured or unrupturedinfrarenal AAAs were included. Conventionalopen repair, non-surgical treatment for AAA(sometimes referred to as ‘best medical treatment’)or surveillance (sometimes referred to as ‘watchfulwaiting’) were the appropriate comparators. Onlystudies reporting at least one of the followingoutcomes were included: 30-day mortality rate;aneurysm-related mortality; all-cause mortality;health-related quality of life (HRQoL); adverseeffects and complications; and reinterventionrates including conversion from EVAR to openprocedure and secondary intervention. Whenappropriate, meta-analysis was employed toestimate a summary measure of treatment effecton relevant outcomes based on intention to treatanalyses.A second systematic review was undertaken toidentify and compare existing cost-effectivenessanalyses of EVAR compared with open surgery andnon-surgical interventions. This review includedsubmissions of economic analyses made by EVARdevice manufacturers.Two new decision models were also developedto inform the review. The first compared thecost-effectiveness of EVAR versus open repairin patients with a large aneurysm (≥ 5.5 cm) forwhom the decision to operate has been taken. Thesecond decision model, complementary to the first,compared options of early surgery (with EVARor open repair), watchful waiting and no surgicalintervention. Both models investigated the costeffectivenessof the strategies in patients of varyingage, aneurysm size and level of operative fitness.Four fitness levels were defined in the analysis,given a patient’s age and aneurysm size: good,moderate, poor and very poor.xiii

Executive summaryxivResultsClinical effectivenessSix RCTs were included in the review. Fourcompared EVAR and open surgery in patients withunruptured AAAs who were fit for open repair.One RCT compared EVAR with non-surgicalmanagement of patients deemed unfit for openrepair. A small RCT compared EVAR and openrepair in patients with ruptured AAAs. There arefive ongoing trials from which results are currentlyunavailable. The limited data reported by theNVD and RETA registries, and the ‘older’ devicesused and non-current data reported by RETA,highlight the importance of the EUROSTAR dataand findings. Thirty-four studies evaluated the roleof patients’ baseline characteristics in predictingthe risks of particular outcomes after EVAR. Threestudies evaluated existing scoring systems and onestudy evaluated the development of a model forassessing risks. However, the majority of the riskmodelling studies investigated specific risk factorsusing multiple regression analysis. The majorityof these studies were based on data from theEUROSTAR registry with likely overlap of patients.Compared with open repair, EVAR reducesoperative mortality (odds ratio 0.35, 95% CI 0.19to 0.63) and aneurysm-related mortality over themedium term (hazard ratio 0.49, 95% CI 0.29 to0.83) but offers no significant difference in allcausemortality at mid-term follow-up. EVAR wasassociated with increased rates of complicationsand reinterventions and these are not offset by anyincrease in HRQoL.There is limited RCT evidence comparing EVARwith non-surgical management in patients unfit foropen repair. EVAR trial 2 found no differences inmortality outcomes between groups but this findingcannot be taken as definitive because substantialnumbers of patients randomised to non-surgicalmanagement crossed over to receive surgical repairof their aneurysm. This may indicate that thebenefits of EVAR over no intervention may requiremore than 4 years of follow-up to become apparent.The results from these trials are complemented bydata from registries, in particular the EUROSTARregistry data relating to devices in current use.Cost-effectivenessThe systematic review of the economic evidenceidentified six published decision models. Of thefive models comparing EVAR and open repair,two were constructed after the operative mortalityresults of the good-quality RCTs were publishedand are considered to be relevant for the decisionin the UK. Both concluded that EVAR was notcost-effective on average at a threshold of £20,000per quality-adjusted life-year (QALY). One modelcompared EVAR with no surgical intervention. Thismodel was constructed before the results of theEVAR trial 2 were published. The model concludedthat EVAR would be on average more cost-effectivethan no surgical intervention in unfit patients ata threshold of £20,000 per QALY. One model wassubmitted by a manufacturer (Medtronic). Thismodel concluded that EVAR was more cost-effectivethan open repair for fit patients at a threshold of£20,000 per QALY.The main findings of the York economicevaluations (base-case models at a threshold of£20,000 per QALY) are:• EVAR is not cost-effective compared with openrepair on average given base-case assumptionsat a threshold of £30,000 per QALY.• Results are very sensitive to model assumptions.EVAR may be more cost-effective than openrepair if the relative costs of the procedurehave fallen, reinterventions are relatively lessfrequent and follow-up surveillance is currentlyless intensive compared with the base-caseassumptions.• Results are sensitive to the baseline risk ofoperative mortality. A subgroup analysisfound that EVAR was likely to be cost-effectivecompared with open repair in patients withpoor operative risk and unlikely to be costeffectivein patients with good operative risk. Avalidated and accepted fitness score is neededto distinguish individual patients by operativerisk.• An exploratory analysis was undertaken toevaluate management options in patients whowould not be considered suitable for opensurgery, that is, in patients of very poor fitness.This model was based on uncertain data aboutthe natural history of untreated aneurysm. Thissuggested that the cost-effectiveness of EVARmay be sensitive to aneurysm size and patient’sage at operation. Further research in theseareas would be important to inform futuremodelling work.• Indicative modelling results suggest that EVARmay be cost-effective for small aneurysms(< 5.5 cm) in some patient groups. OngoingRCTs will provide further evidence relatingto these patients. A review of the currentguideline that aneurysms should not be

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48operated on if less than 5.5 cm should then beconsidered.ConclusionsImplications for service provisionBased on the results of this assessment of clinicaland cost-effectiveness, and using a set of basecaseassumptions, open repair is likely to beconsidered cost-effective compared with EVARon average in patients considered fit for opensurgery. Cost-effectiveness may vary with fitness.EVAR is likely to be more cost-effective than openrepair for patients at higher risk of operativemortality. There is considerable uncertainty inthis analysis, in particular concerning the relativecost of procedures and rate of reinterventions.An exploratory study suggested that EVAR maybe more cost-effective than medical treatment orwatchful waiting for some groups of patients unfitfor open repair, depending on age and aneurysmsize. Evidence does not currently support EVAR forthe treatment of ruptured aneurysms.Suggested research priorities• Further follow-up of the existing UK trials(EVAR trial 1, EVAR trial 2) should beundertaken.• The relative procedure costs and device costsshould be investigated further.• Opportunities for individual patient metaanalysisof all RCTs relating to EVAR should besought.• Further research is needed on the ratesof late complications, reinterventions andaneurysm-related mortality after EVAR, inparticular those associated with the most recentgeneration of devices.• The optimal surveillance policy followingEVAR should be investigated.• The extent to which the relative treatmenteffect of EVAR on operative mortality can beassumed constant across subgroups of patientsshould be further investigated.• Research is required into how to implementthe best available risk scoring systems for themanagement of AAA into decision-making inroutine clinical practice.• Research is required into the natural historyof untreated AAA to determine more reliablywhen surgical intervention is optimal. Theanalysis should investigate the impact ofdifferent levels and determinants of patientfitness as well as aneurysm size and anatomy.• A well-defined and well-conducted RCT ofEVAR versus watchful waiting, reflectingcurrent clinical practice, is warranted. However,given the difficulties of conducting RCTs in themanagement of AAA it is probably advisablethat the collection of data through the existing,established registries in the UK, particularlyRETA (for EVAR) and NVD (for open repair),should be continued.xv© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 1BackgroundDescription of healthproblemAortic aneurysms develop when weakening of thevessel wall, often due to atherosclerosis, causes itto bulge, forming a balloon-like projection. Thisin turn leads to further stretching of the vesselwall and an increase in tension. Eventually, thevessel wall may rupture, leading to massive internalbleeding.Most aneurysms occur in the abdominal section ofthe aorta. An abdominal aortic aneurysm (AAA) isdefined as an enlargement of the aorta to 1.5 timesor more of its normal diameter or of greater than3 cm. Most AAAs occur in the lower (infrarenal)part of the abdominal aorta.Symptoms that may occur as an aneurysm enlargesinclude a pulsating sensation in the abdomen, backpain and abdominal pain, which may spread to theback. Symptomatic AAAs require rapid medicalattention. Rupture of an AAA is associated with amortality rate of about 80%; even when patientsundergo emergency surgery, only about half survivebeyond 30 days. 1 The risk of rupture increases withthe size of the aneurysm. For example, in the UKSmall Aneurysm Trial (UKSAT) and associatedmonitoring study, 2 the number of ruptures per100 patient-years was 0.3, 1.5 and 6.5 for patientswith AAAs of diameter ≤ 3.9 cm, 4.0–4.9 cm and5.0–5.9 cm respectively. The rate of rupture may beup to 25% annually for aneurysms with diameters> 6 cm, and a number of studies indicate thatwithout surgery the 5-year survival rate for patientswith aneurysms > 5 cm is about 20%. 3The main risk factors for AAAs include age, highblood pressure, male sex, smoking and familyhistory. Because most AAAs are asymptomaticit is difficult to estimate the prevalence of thecondition, but screening studies in the UK haveestimated a prevalence of 1.3–12.7% depending onthe age group studied and the definition of AAA. 3AAAs are about three times more common in menthan in women. 1 The incidence of symptomaticAAA in men is approximately 25 per 100,000at age 50 years, increasing to 78 per 100,000 inthose older than 70 years. The overall incidence© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.of AAAs has increased in recent years and is likelyto increase further in line with the ageing of thegeneral population.Most AAAs are detected by chance during clinicalexamination or investigation (e.g. ultrasound orradiography) for other conditions. Ultrasoundscreening of the population for early detectionof AAAs has been extensively evaluated. In theUK the large Multicentre Aneurysm ScreeningStudy RCT found that screening men aged 65–74reduced the risk of aneurysm-related death by42% over 4 years. 4 Screening was marginally costeffectiveover 4 years and cost-effectiveness wasexpected to improve substantially over a longerperiod. 5 National screening programmes are underconsideration by the four UK health departmentsat the time of writing.Current service provisionAAAs can be treated by surgical repair to preventrupture. Conventional (‘open’) surgical repairinvolves making a large incision in the abdomenand inserting a prosthetic graft to replace thedamaged section of the aorta. Open repair of AAAcarries substantial risk of mortality and morbidity,particularly because many patients with an AAAhave significant comorbidities (e.g. heart or kidneydisease) that reduce their fitness for surgery. Openrepair can also be performed laparoscopically,either by hand-assisted laparoscopic surgery orby totally laparoscopic surgery (TLS). Guidanceissued by the National Institute for Health andClinical Excellence (NICE) 6 states that, althoughthere is adequate evidence of the safety and efficacyof these laparoscopic techniques, the technicaldemands are such that such procedures should notbe used without special arrangements for consentand for audit or research.In current UK clinical practice, elective surgery isgenerally recommended for aneurysms > 5.5 cm indiameter, as well as for those of diameter > 4.5 cmwith an increase in size of > 0.5 cm in the last 6months. The UKSAT 7 and ADAM 8 trials indicatedthat there was no mortality advantage of immediate(open) surgical repair over imaging surveillance1

Background2in patients with aneurysms of < 5.5 cm diameter.Current guidelines recommend that patients withasymptomatic aneurysms < 4.5 cm are followedup with ultrasonography every 6 months, whereasaneurysms of 4.5–5.5 cm are followed up every 3 or6 months.Approximately 25% of patients with an AAArequiring surgery are considered unfit foropen surgery. 9 Such patients will be kept undersurveillance with an option to defer surgery or adecision to rule out surgery entirely. As age, fitnessand the untreated risk of rupture are evolvingover time, the option to defer makes the decisioncomplex and dynamic. 10,11 It is unclear what theoptimum management policy should be in patientsconsidered unfit for open surgery. It may be thata policy whose aim is to try and improve patientfitness might be effective and patients may beoffered medical therapy to reduce risk factors, forexample smoking cessation and blood pressurereduction therapy, but such a policy has not yetbeen evaluated.Description of technologyunder assessmentEndovascular aneurysm repair (EVAR) is aminimally invasive technique that involves placinga stent graft prosthesis at the site of the aneurysm. 12The stent graft is inserted through a small incisionin the femoral artery in the groin, carried to thesite of the aneurysm using catheters and guidewiresand placed in position under radiographicguidance. Once in position the stent graft isdeployed and anchored to the wall of the aortausing a variety of fixing mechanisms. The graftis stronger than the weakened aorta and allowsblood to pass through it without creating pressureon the aneurysm. The main types of endovascularstent grafts are aortic tube grafts (no longer usedin the UK), aorto-uni-iliac grafts and aorto-bi-iliac(bifurcated) grafts, with most procedures in theUK using bi-iliac stents. EVAR is carried out undergeneral, regional or local anaesthesia.EVAR has been used to treat patients both classifiedas fit for open repair and classified as unfit. It isused both as an elective procedure and to treatsymptomatic and ruptured aneurysms. However, itmust be emphasised that EVAR is not suitable forall patients. Patient suitability for EVAR dependson the morphology of the aneurysm. This isassessed by diagnostic imaging, usually computedtomography (CT) scanning and occasionallyangiography or magnetic resonance imaging(MRI). In an unselected population of patientswith AAA only 55% did not have an absolutemorphological contraindication to EVAR. 13Potential advantages of EVAR over open repairinclude reduced time under general anaesthesia,elimination of the pain and trauma associated withmajor abdominal surgery, reduced length of stay inthe hospital and intensive care unit, and reducedblood loss. 14 Potential disadvantages include thedevelopment of endoleaks, which occur whenblood continues to flow through the aneurysmbecause the graft does not seal completely orbecause of backfilling of the aneurysm from othersmall vessels arising from the aneurysm wall. Thus,although open repair does not require any specialfollow-up, patients who have undergone EVARrequire regular CT scans to check for the presenceof late endoleaks. 14 In addition, if the EVARprocedure is unsuccessful or complications ariseduring the procedure, conversion to open repairmay be necessary in patients initially consideredunfit for open surgery. 14Prices of endovascular stent graftsEndovascular stents are not homogeneousproducts. There are a number of differentendovascular stent devices made by differentcompanies, each with different costs. This is furthercomplicated by the fact that different patientswho may be fitted with the same company’s devicemay require different numbers of extensions. Thecompanies who produce these devices also offerdifferent pricing structures (e.g. some charge aprice per patient regardless of the number ofextensions required whereas others charge basedon the parts required). If the price per patientis not fixed then ideally the mean price per caseshould be calculated based on an assessment ofthe expected number of extension parts required,which in turn depends on the population casemix. There is also the added complication thatindividual hospitals often do not actually pay thelist price, with manufacturers offering discounts.These considerations make the process of costing adevice for the economic evaluation complex.The NICE Guide to the Methods of TechnologyAppraisal 15 states that: ‘Where the actual price paidfor a resource may differ from the public list price(for example, pharmaceuticals, medical devices),the public list price should be used’.Commercial-in-confidence information on theprice of different models of stent grafts andacademic-in-confidence information on the use

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48and cost of endovascular devices in EVAR trial 1has been removed.Risk score measuresfor surgical riskBefore any surgical procedure is undertaken thefitness of the patient needs to be assessed. Riskscore measures provide numerical scores that havebeen calculated based on a number of patientfactors (e.g. age, gender) that are considered topredict the risk for survival of surgery, with higherscores indicating greater predicted risk. Low riskscores are not the same as no risk. 16 Risk scoremodels vary in complexity and accuracy but enablecomparisons of outcomes to be made betweengroups of patients, institutions and individualsurgeons whilst taking into account patient-relatedfactors and comorbidity. 16 Although there are alarge number of tools in use to measure operativerisk, there is no ideal tool and those in use havemany limitations. Measures are used largely topredict risk in various patient groups rather thanin individuals, and often the cut-off points betweenhigh and low risk are based on costs and thecomplexity of providing treatment to correct therisk rather than on the risk itself. 17The main risk scores used in clinical practice, withtheir roles in predicting risk for EVAR, are outlinedbelow.American Society ofAnesthesiologistsThe American Society of Anesthesiologists(ASA) classification system is widely used and,although it was not originally designed to estimateoperative risk, many medical professionals useit as a means of preoperative risk assessmentand some have identified it as a predictor ofpostoperative morbidity and mortality. 18 ASAclassifies preoperative physical status, allocatingpatients to one of five categories based on generalmedical history and examination and not requiringany specific investigations: class I (normal healthypatient), class II (mild systemic disease), class III(severe systemic disease but not incapacitating),class IV (incapacitating systemic disease that is athreat to life) and class V (moribund, not expectedto survive 24 hours with or without operation).Generally, ASA is effective in predicting mortalitywhen used alone or in conjunction with otherparameters, as postoperative mortality rates risesteadily with the ASA grade. 19 However, there isthe potential for interobserver subjective error© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.as it remains a semisubjective assessment by theAnesthesiologist based on patient comorbidities. 18Acute Physiology andChronic Health EvaluationThe Acute Physiology and Chronic HealthEvaluation (APACHE) presents an overall scorefor physiological variables, age points and chronichealth and has been used extensively in theintensive care setting. It aims to classify patientson the basis of the severity of illness to facilitatecomparison of outcomes, to facilitate the evaluationof new therapies and as an indicator of dailyprogress. APACHE II measures are based on 12physiological and laboratory factors in addition toage and previous health status.The APACHE-AAA model was developed andinternally validated specifically to predict outcomein postoperative AAA patients who are managedin the intensive care unit. 20 However, this modelcannot be used for preoperative decision-making. 21Bayesian risk modelling(Customized Probability Index)The Customized Probability Index (CPI) accountsfor significant clinical risk factors (cardiac andnon-cardiac) and current medication use inpredicting all-cause perioperative mortality inpatients undergoing all types of open vascularsurgery. It identifies nine independent predictorsof perioperative mortality: type of vascular surgery,ischaemic heart disease, congestive heart failure,previous stroke, hypertension, renal dysfunctionand chronic pulmonary disease associated withincreased risk, and beta-blocker and statin useassociated with lower risk. Risk is calculated usingthe sum of scores for surgical risk (0–46 points),medical history (0–67 points) and cardioprotectivemedication (statins –10 points and beta-blockers–15 points). 22 The EVAR trial participants 23 wereassessed for fitness based on clinicians’ decisionsusing clinical parameters that were integrated intothe calculation of the modified CPI.Charlson Comorbidity IndexThe Charlson Comorbidity Index (CCI) is aweighted index of comorbidity (number andseriousness of comorbid diseases) that providesa total score as follows: 1 = myocardial infarct,congestive heart failure, peripheral vasculardisease, cerebrovascular disease, dementia, chronicpulmonary disease, connective tissue disease,ulcer disease, mild liver disease and diabetes;3

Background42 = hemiplegia, moderate or severe renal disease,diabetes with end organ damage, any tumour,leukaemia and lymphoma; 3 = moderate or severeliver disease; 6 = metastatic solid tumour and AIDS.A study 24 looking at survival rates of patients withelective open AAA repair reported the CCI as asignificant independent predictor of lower survival.Comorbidity Severity ScoreThe Comorbidity Severity Score (CSS) wasdeveloped specifically for EVAR risk stratificationand includes a comorbidity severity score andan anatomic factor severity score, which includescardiac disease, pulmonary disease, renal disease,hypertension and age. The Modified ComorbiditySeverity Score (M-CSS) has been found to bevalid for predicting risk in open repair. 25 Whenrisk scores for open repair were applied to EVARpatients, observed mortality was different, but thiswas only statistically significant for the highest riskscores.Glasgow Aneurysm ScoreThe Glasgow Aneurysm Score (GAS) estimatespreoperative risk profiles that predict perioperativeoutcomes after open repair and more recently hasbeen shown to predict perioperative and long-termmortality after EVAR. 26 GAS is calculated using theformula: risk score = (age in years) + (7 points formyocardial disease) + (10 points for cerebrovasculardisease) + (14 points for renal disease) + (17 pointsfor shock) (not necessarily applicable when electivesurgery patients). The GAS separates patients intolow- or high-risk groups, with high-risk patientsreceiving a risk score of ≥ 79 points and potentiallybeing considered unsuitable for surgery. 27Goldman Cardiac Risk IndexThe revised Goldman Cardiac Risk Index (CRI;Detsky Index) includes six independent variables.An evaluation of cardiac risk indices for patientsundergoing non-cardiac surgery carried out byGilbert et al. 28 compared the Detsky Index withthe Goldman Index and two other indices. Eachindex was found to provide a statistically significantdegree of stratification (p < 0.001) and areasunder the receiver operating characteristic (ROC)curves were similar. The models were significantlybetter than chance for predicting myocardialinfarction and death. However, although,generally, the indices were useful in providingclinical information about risk, the accuracy of themeasures was limited. 28Hardman scoring systemsThe Hardman Prognostic Index includes fiverisk factors: age > 76 years, history of loss ofconsciousness, electrocardiogram evidence ofischaemia, haemoglobin < 9 g/dl and serumcreatinine > 0.19 mmol/l. A small study 29 comparedthe predictive value of the Hardman Index inpatients undergoing EVAR and open repair andfound that mortality rates increased with risingHardman scores for both open and EVAR patients.Leiden score/modifiedLeiden scoreThe Leiden score is based on age, gender, presenceof myocardial infarction, ST-segment depression,congestive heart failure, renal disease andpulmonary disease, and centre-specific averagesurgical mortality. The modified Leiden score (M-LS) is based on the same variables but ST-segmentdepression and centre-specific average surgicalmortality are not included and more points aregiven for severe renal disease. Both the Leidenscore and M-LS predicted postoperative mortality,although their accuracy in predicting postoperativecomplications is somewhat lower. 30POSSUM/V-POSSUMPOSSUM (Physiological and Severity Score for theEnumeration of Mortality and Morbidity) has beenwidely used for assessing outcomes by risk-adjustedanalysis in the UK. 19 It includes a physiologicalassessment and a measure of operative severity.The physiological assessment includes 12physiological variables, divided into four grades,which are present at the time of surgery: age,cardiac history, respiratory history, blood pressure,pulse rate, Glasgow coma score, haemoglobin,white blood count, serum urea, serum sodium,serum potassium and electrocardiogram. Theoperative severity section includes six variables,divided into four grades: operative severity,multiple procedure, total blood loss, peritonealsoiling, presence of malignancy and mode ofsurgery.POSSUM has shown favourable results formortality and morbidity risk prediction andcomparative surgical audit, but it does havelimitations. In particular, this model and theP-POSSUM model overestimate mortality for lowriskprocedures. 31 An assessment of the validityof V-POSSUM (Vascular-POSSUM) and rupturedAAA-POSSUM models concluded that the twoscoring systems were not effective predictors ofdeath after ruptured AAA. 32

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Vascular-Biochemistry andHaematology Outcome ModellingThe Vascular-Biochemistry and HaematologyOutcome Modelling (V-BOHM) uses data obtainedbefore operation to predict outcome, includinghaemoglobin level, white blood count, urea,sodium, potassium and age on admission. Thismodel was developed to provide accurate riskprediction for both elective and non-elective AAAsurgery (open repair), without the problems oftenexperienced with missing data. An evaluationof the efficacy of the V-BOHM in 2718 patientsfound that the model, which also included age andgender as risk factors, was effective in predictingsurgical mortality after both open elective and nonelectiveAAA repair. 33OthersA number of other risk score measures are usedin clinical practice, including the British UnitedProvident Association (BUPA) operative grade,Eagle score, Hospital Prognostic Index andPrognostic Nutritional Index.5© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 2Definition of decision problemDecision problemFor patients who are suitable for aneurysm repair,is EVAR or open repair more effective and costeffective?More generally, what is the optimummanagement strategy for patients with a diagnosisof AAA? Immediate elective surgery with openrepair, immediate elective surgery with EVAR,surveillance with an option to defer surgery, or adecision to rule out surgery entirely?Overall aims and objectivesof assessmentThe objectives of this assessment are to determinethe clinical and cost-effectiveness of endovascularstent grafts for repair of infrarenal AAAs inpatients at varying levels of risk, including thosewho are appropriate for open repair and thosewho are not. The assessment will build on theinformation already available, including recentsystematic reviews. 12,34–36 A particular objective isto seek evidence to clarify areas of uncertainty,for example about longer-term outcomes, aboutthe variables and risk factors that influence theeffectiveness and safety of EVAR and whetherthere are subgroups of patients for whom EVARis particularly appropriate. Recommendations forfurther research will reflect identified gaps in theevidence base.The specific objectives of the cost-effectivenessanalysis are:• to structure an appropriate decision modelto characterise patients’ care and subsequentprognosis and the impacts of alternativetherapies• to populate this model using the mostappropriate data identified systematically frompublished literature and routine data sources• to relate intermediate outcomes to final healthoutcomes, expressed in terms of qualityadjustedlife-years (QALYs)• to estimate the mean cost-effectiveness ofEVAR compared with standard care (openrepair or non-surgical management), based onan assessment of long-term NHS and personalsocial service costs and quality-adjusted survival• to report the cost-effectiveness of alternativetreatments for specific subgroups of patient,consistent with available evidence; this mayinclude cost-effectiveness according to patients’underlying risk of particular clinical events• to characterise the uncertainty in the dataused to populate the model and to present theuncertainty in these results to decision-makers.Confidential informationThis report contains reference to confidentialinformation provided as part of the NICE appraisalprocess. This information has been removedfrom the report and the results, discussions andconclusions of the report do not include theconfidential information. These sections are clearlymarked in the report.7© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 3Assessment of clinical effectivenessMethods for reviewingclinical effectivenessSearch strategyRecent systematic reviews by Drury et al. 34 andLederle et al. 35 were used to identify randomisedcontrolled trials (RCTs) and other clinical studies.Additional searches were conducted to identifyrecent RCTs (2005–7), publications relating tonamed registries and studies investigating baselinerisks. Searches were not restricted by language orstudy design and studies written in any languagewere eligible for inclusion in the review.To identify systematic reviews and guidelines thefollowing databases and web pages were searched/scanned: Cochrane Database of SystematicReviews, Database of Abstract of Reviews of Effects(DARE), Health Technology Assessment (HTA)database, National Library for Health (NLH)National Library of Guidelines, National GuidelineClearinghouse, NICE web pages.The following bibliographic databases weresearched to identify RCTs (2005–February 2007),risk modelling studies and papers based onregistry data: BIOSIS Previews, ® CumulativeIndex to Nursing and Allied Health Literature(CINAHL), Cochrane Central Register ofControlled Trials, EMBASE, ISI Proceedings,MEDLINE, ® MEDLINE ® In-Process & Other Non-Indexed Citations, Science Citation Index andZetoc Conferences. Search strategies are given inAppendix 1. Searches to identify any ongoing trialswere carried out using Clinicaltrials.gov, CurrentControlled Trials and the National ResearchRegister.Regular current awareness searches were carriedout during the review using both Science Directand Zetoc. Search alerts were set up for a numberof topic-specific journals: Annals of Vascular Surgery,Asia Pacific Journal of Thoracic and CardiovascularSurgery, Cardiovascular Surgery, European Journalof Vascular Surgery, European Journal of Vascularand Endovascular Surgery, Interactive Cardiovascularand Thoracic Surgery, Italian Journal of Vascularand Endovascular Surgery, Journal of EndovascularTherapy, Journal of Thoracic and Cardiovascular© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.Surgery, Journal of Vascular Surgery, OperativeTechniques in Thoracic and Cardiovascular Surgery,Perspectives in Vascular Surgery and EndovascularTherapy, Seminars in Thoracic and CardiovascularSurgery, Seminars in Vascular Surgery and Vascularand Endovascular Surgery.In addition, OvidAutoAlerts were created inboth the MEDLINE and EMBASE databases tonotify the review team of papers with EVAR in thetitle, original title or abstract. Current awarenesssearches were continued until February 2008.Inclusion and exclusion criteriaTwo reviewers independently screened all titlesand abstracts. Potentially relevant full papermanuscripts were obtained when possible, and therelevance of each study was assessed independentlyby two reviewers in accordance with the criteriabelow. Discrepancies were resolved throughdiscussion or by referral to a third reviewer whennecessary. Studies that did not fulfil all of thecriteria were excluded, with reasons for theirexclusion documented.PopulationPatients with asymptomatic or symptomatic,ruptured or unruptured infrarenal AAAs thatwere anatomically and clinically suitable forendovascular stent graft repair (EVAR) wereincluded. The study authors’ definitions ofaneurysm status and suitability for EVAR were used.Studies of patients with aneurysms of any size wereincluded.InterventionsStudies of elective or emergency EVAR of infrarenalAAAs, using uni-iliac or bi-iliac stent grafts, wereincluded. It was recognised that not all devicesevaluated in the research literature would havea CE mark and that several devices would haveundergone a number of changes. It was alsorecognised that manufacturers’ devices would havevarying indications and contraindications for use.Hence, studies of any EVAR device were eligiblebut, when data allowed, analysis focused on devicescommonly used in current UK practice.9

Assessment of clinical effectiveness10ComparatorsStudies in which the comparator was one of thefollowing were included:• For patients in whom conventional open repairwas a treatment option (according to studyauthors’ criteria) conventional open repair wasthe appropriate comparator.• For patients in whom conventional open repairwas not a treatment option (according to studyauthors’ criteria) the appropriate comparatorwas non-surgical treatment for AAA (sometimesreferred to as ‘watchful waiting’). Suchtreatment will vary across studies but willnormally represent best medical care andwill typically include a range of strategies tomanage vascular risk factors, for examplesmoking cessation, blood pressure reductionand statin therapy.OutcomesOnly studies reporting at least one of the followingoutcomes were included:• 30-day mortality rate• aneurysm-related mortality• all-cause mortality• health-related quality of life (HRQoL)• adverse effects and complications; thisincluded aneurysm-related outcomes suchas rupture and events specific to EVAR, e.g.frequency of endoleaks and device migration;major morbidity, for example cardiac events,was also assessed• reintervention rates including conversionfrom EVAR to open procedure and secondaryintervention.Study designsEstimates of the treatment effect and safetyoutcomes of EVAR were derived from RCTs andlarge registries of relevance to UK practice. Theregistries used were the Registry of EndovascularTreatment of Abdominal Aortic Aneurysms (RETA)and the European Collaborators on Stent GraftTechniques for Abdominal Aortic Aneurysm Repair(EUROSTAR) for EVAR, and the National VascularDatabase (NVD) for open surgery.To identify criteria for selecting patientsappropriate for EVAR, studies that modelled thespectrum of risk were also reviewed. Risk modellingstudies were specific to AAA, focused on risk ofmortality following EVAR and used appropriatestatistical modelling techniques (e.g. Kaplan–Meier survival analysis, multiple linear or logisticregression or Cox proportional hazards analysis).Studies were required to be based on a trial,registry or a series of at least 500 patients fromdeveloped countries of relevance to UK practice.The review protocol specified a minimum of 1000patients; this was reduced to 500 during the reviewprocess to allow inclusion of some of the mostclinically relevant studies.Data extraction strategyData relating to both study design and quality wereextracted by one reviewer, using a standardiseddata extraction form, and checked by a secondreviewer. Discrepancies were resolved by discussion,with involvement of a third reviewer whennecessary. For studies with multiple publications,that with the greatest number of participants orthe longest follow-up or the latest publicationpresenting the largest amount of outcome datawas extracted. For registries this was interpretedto mean the latest report covering all patients inthe registry; publications based on an analysisof registry data that were not reports of theregistry as a whole were included in the review forcompleteness but were not data extracted unlessthey contained unique data on all patients in theregistry. Data were extracted on study details (e.g.study identifier/EndNote ID, author, year, country,setting, number of participants and fitness),patient characteristics (e.g. age, gender, causal/riskfactors, comorbidities, aneurysm size/anatomy),intervention (type of stent graft), comparison(details of open repair or medical management),study quality (RCTs and risk model studies) andreported outcomes relating to efficacy and safetyas specified above. Careful note was made ofdefinitions used by study authors in relation tofitness for surgery and AAA-related mortality.Quality assessment strategyThe quality of the individual RCTs and riskmodel studies was assessed by one reviewer andindependently checked for agreement by a secondreviewer. Any disagreements were resolved byconsensus and, when necessary, a third reviewerwas consulted. The quality of RCTs was assessedusing standard checklists 37 that were adaptedto incorporate topic-specific quality issues. Thequality of risk models was assessed using a checklistadapted by the authors from a checklist used in aprevious systematic review of prognostic models. 38The quality of audit/registry data was not assessedbecause the included registries were chosen forrelevance and prespecified in the protocol.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Data analysisData extracted from the studies were tabulatedand discussed in a narrative review. The results ofthe quality assessment were tabulated and, whenpossible, the effects of study quality on effectivenessdata and the findings of the review were discussed.When appropriate, meta-analysis was employed toestimate a summary measure of treatment effecton relevant outcomes based on intention to treat(ITT) analyses. Meta-analysis was carried out usingfixed-effects models using Review Manager 4.2. Aspreadsheet developed by the MRC Clinical TrialsUnit, London, was used to estimate hazard ratioswhere necessary. 39 Heterogeneity was exploredthrough consideration of the study populations,methods and interventions, by visualisation ofresults and, in statistical terms, by the chi-squaredtest for homogeneity and the I 2 statistic. Riskmodelling studies that investigated specific riskfactors were interpreted with the aid of charts. Eachchart represented one variable and one outcomeand displayed the studies that had investigatedthis factor. Using the measure given in the studyeach study was plotted on the chart as finding thevariable to be an independent risk factor or not.Summary statements were generated from thecharts, indicating the likelihood of a given variablebeing a risk factor for a given outcome.Results of the review ofclinical effectivenessQuantity and quality ofresearch availableIncluded RCTsFigure 1 presents a flow chart of studies throughthe review process. Six RCTs were included inthe review. Four of these (DREAM, 40,41 EVAR trial1 23,42,43 and the studies by Cuypers et al. 44 andSoulez et al. 45 ) compared EVAR with open surgeryin patients with unruptured AAAs who were fit foropen repair. One RCT (EVAR trial 2 46 ) comparedEVAR with non-surgical management of patientsdeemed unfit for open repair. A small RCT byHinchliffe et al. 47 compared EVAR with open repairin patients with ruptured AAAs.Titles and abstractsidentified and screenedn = 4691Excluded n = 4012Not relevant n = 3862 aRecords of research in progress n = 150Full copies retrieved andscreened for inclusionn = 679Excluded n = 549Patient group not AAA n = 19RCT but not EVAR vs open or non-surgical n = 8Registry other than RETA, EUROSTAR or NVD n = 3Risk model but not modelling patient risk following EVAR n = 26Risk model but outcome not relevant n = 2Risk model with fewer than 500 patients n = 94Not RCT, registry or risk model n = 392Duplicate n = 5Total number of studies included n = 43RCTs n = 6 (19 publications)Risk models n = 34 (36 publications)Registries n = 3 (75 publications) bFIGURE 1 Flow chart of studies through the review process. a, Excluded based on title and abstract; b, most registry publications werenot data extracted (see Data extraction strategy).11© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness12TABLE 1 Quality assessment results for RCTsIntention totreat analysisPowercalculationreportedWithdrawalsor exclusionsaccounted forEligibilitycriteriareportedBaselinecharacteristicscomparablebetween groupsOutcomeassessor blindedAdequateconcealmentof treatmentallocationTruerandomisationStudy (mainpublication)DREAMYes Yes Yes Yes Yes Yes Yes Yes2005 41BlankensteijnCuypers 2001 44 Unclear Unclear Unclear Yes Yes Yes Yes YesEVAR trial 2 Yes Yes Yes Yes Yes Yes Yes Yes2005 46EVAR trial 1 Yes Yes Yes Yes Yes Yes Yes Yes2005 43Hinchliffe 2006 47 Unclear No Unclear Yes Yes Yes Yes YesSoulez 2005 45 Unclear Unclear Unclear Yes Yes Yes No Unclear

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48The results of the quality assessment of theincluded RCTs are presented in Table 1. The mainRCTs, DREAM, 41 EVAR trial 1 43 and EVAR trial2, 46 were all of high quality (positive answers to allquality questions). Some methodological aspectsof the remaining RCTs were unclear based on thepublished reports. The study of EVAR versus openrepair for patients with ruptured AAAs 47 lackedadequate concealment of treatment allocation,perhaps reflecting the ethical and practicalproblems of conducting an RCT in a setting ofemergency surgery. The RCT by Soulez et al. 45 didnot report a sample size calculation and probablylacked statistical power to detect differences inmortality and related outcomes.In addition to methodological quality issues, theseRCTs have a number of limitations that may affecttheir usefulness in assessing the current clinicaleffectiveness of EVAR relative to open repair andnon-surgical management. Of the four RCTs thatcompared EVAR and open repair in patients withunruptured aneurysms, those of Cuypers et al. 44and Soulez et al. 45 were small studies and were notdesigned to assess hard clinical end points such asmortality; furthermore, the study of Cuypers et al.was limited to 1 month of follow-up. Hence, theanalysis of EVAR versus open repair for unrupturedAAAs concentrated on data from the larger RCTs.The major trials comparing EVAR with open repair,DREAM 40,41 and EVAR trial 1, 42,43 randomisedpatients between November 2000 and December2003 and between September 1999 and August2004 respectively. Thus, the devices used and otherdetails of the procedures may not represent currentbest practice. Published results from the two RCTsrepresent relatively short periods of follow-up (2years for DREAM and 4 years for EVAR trial 1).The main analyses of EVAR trial 1 were publishedin 2004 for 30-day operative mortality 42 and in2005 for 4-year follow-up results 43 and coveredpatients randomised up to December 2003. The4-year results for patients randomised up to August2004 were included in a publication analysingresults by patient fitness. 23 These data were notincluded in the analyses of mortality outcomes inthis review because this was a secondary publicationwith limited details and because the additionalpatients were randomised after the official closeof recruitment. Finally, the sample size calculationfor DREAM was based on a primary end pointof short-term mortality and complications, andthe trial’s power to detect differences in follow-upoutcomes is unclear.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.The other relevant comparison is between EVARand continued non-surgical management ofpatients considered unfit or unsuitable for openrepair. The only RCT to have addressed this issueis EVAR trial 2. 46 Although this was a high-qualityRCT in terms of design and methodology, therewere problems with its execution. There was amedian delay of 57 days between randomisationand procedure in the EVAR arm and 14 patientsin this group died before operation (including sixfrom AAA rupture). In total, 47 patients assignedto non-surgical management received surgicalaneurysm repair (including 12 who received openrepair despite having been classified as unfit forthis procedure). These factors complicate theanalysis and interpretation of this trial.The evidence base for EVAR for patients withruptured AAAs is currently limited to one smallpilot trial. 47 The sample size calculation for thistrial was based on recruiting 100 patients, butonly 32 patients were randomised, which makesit difficult to draw any firm conclusions from thetrial. However, the study showed that it is possibleto conduct a randomised trial in this setting.The ongoing Amsterdam Acute Aneurysm Trial,discussed in the following section, should providefurther evidence in due course. 48Ongoing RCTsWe received information from investigators of fivepotentially relevant ongoing RCTs who we hadcontacted to request further details and any datathat the investigators were willing to include in ourreview.ACE 49 is a French RCT comparing EVAR and openrepair in patients aged 50 years and older withan AAA measuring ≥ 5 cm in diameter (≥ 4 cmif rapidly growing). The primary outcomes aredeath and major morbidity and the trial enrolled600 patients. The trial started in January 2003with an expected completion date of January2006. The investigators informed us of a possiblefirst publication in January 2008 (V David,Hôpital Henri Mondor, Creteil, France, personalcommunication, 2008) but further details have notbeen made available.The Amsterdam Acute Aneurysm Trial is an RCTcomparing EVAR and open repair in patientswith a ruptured AAA. A paper describing thebackground, methods and design of the studyhas been published. 48 The primary outcome is acomposite of death and severe morbidity assessedin hospital and at 30 days, 3 months and 6 months13

Assessment of clinical effectiveness14postoperatively. Secondary outcomes includeHRQoL, length of intensive care stay and costeffectiveness.The calculated sample size was 40patients per group. The original scheduled enddate for the trial was August 2008, but this has nowbeen extended to October 2010 (www.controlledtrials.com/ISRCTN66212637,accessed 17 August2009).OVER (Open surgery Versus Endovascular Repair)is a large US RCT comparing EVAR and openrepair in patients aged 50 years and above withan AAA measuring ≥ 5 cm in diameter (≥ 4.5 cm ifexpanding rapidly). 50 The primary outcome is allcausemortality. OVER has an anticipated durationof 9 years and the planned sample size is 900patients. The expected completion date is October2011.NExT ERA (National Expertise Based Trial ofElective Repair of Abdominal Aortic Aneurysms)was a planned pilot study for a national expertisebasedRCT comparing EVAR and open repairin Canada. 51 In November 2007 the investigatorinformed us that the study had been abandoned .(T Mastracci, Hamilton Health Sciences, Hamilton,ON, Canada, personal communication).CAESAR (Comparison of Surveillance VersusAortic Endografting for Small Aneurysm Repair)is an RCT conducted in Italy comparing EVARwith surveillance (and eventual treatment) inpatients with AAAs of diameter 4.1–5.4 cmsuitable for EVAR. The design of the study hasbeen published. 52 The primary outcome is allcausemortality. Secondary outcomes includeaneurysm-related mortality, rupture, perioperativeor late complications, conversion to open repair,complications associated with late treatment andHRQoL. A cost analysis is also included. Patientsassigned to surveillance are considered for surgeryif the aneurysm reaches 5.5 cm in diameter, growsrapidly (> 1 cm/year) or becomes symptomatic. Theplanned sample size is 740 patients. In November2007 the investigators informed us that 325patients had been enrolled and results were notexpected until the end of 2008 (F Verzini, OspedaleS. Maria Misericordia, Perugia, Italy, personalcommunication).Included registriesBecause of the limited data available from RCTs,and the need for long-term data on safety andefficacy for larger numbers of patients, registrydatabases were also included in the review. UnlikeRCTs, which are not powered to allow ad hoccomparisons between subgroups, registries providethe opportunity for various types of secondaryanalysis to be carried out on a large number ofpatients. They may also report more realistic resultsthan RCTs as registry data are obtained from arange of clinical institutions with varying levels ofexperience and expertise. Indeed, there is evidenceto support the validity of registry data, and thatsuch data provide a true representation of a crosssectionof patients, methods and hospitals. 53The three prespecified registries included in thereview were described in six reports. Two were ofEVAR procedures (EUROSTAR 54,55 and RETA 56–58 )and one was of open repair (NVD 16 ).Results from RETA were included in two papers;one reported short-term (30-day) outcome 58 andthe other presented mid-term results to 5 years. 56Data were also presented in an unpublishedreport 57 prepared on behalf of the Vascular SurgicalSociety of Great Britain and Ireland and the BritishSociety of Interventional Radiology. Data for theNVD registry were reported in the Fourth NationalVascular Database Report, 16 published on behalf ofthe Audit and Research Committee of the VascularSociety of Great Britain and Ireland. EUROSTARdata were identified through the progress reportfor endografts in current use, prepared by theEUROSTAR Data Registry Centre, 54 and theregistry’s unpublished protocol paper.Risk modelling studiesA total of 34 studies 23,59–91 evaluated the effect ofbaseline characteristics on the risks of particularoutcomes after EVAR (Table 2).The majority of the studies were based on datafrom the EUROSTAR registry. These studies ofteninvestigated a range of potential risk variablessuch as age and gender and often focused on theinvestigation of one particular risk factor such asdiabetes. However, as there is likely to be overlapof patients between these studies, the number ofstudies reporting the significance of a factor is notalways useful as a guide to the robustness of theevidence. Seven studies 61,62,78,79,85,86,90 are US basedand need to be interpreted within the context ofdifferences in clinical practice between the USAand UK settings. One study was based on anAustralian national audit 60 and one study analyseddata from the UK EVAR trials 1 and 2. 23A further caveat concerns the follow-up periodof the studies included in this section. Generallythe studies cover a period of 5–10 years, although

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 2 Overview of risk modelling studiesType of studyStudy details Data source Study datesDevelopmentof a riskassessmentalgorithmInvestigationof specific riskfactorsEvaluation/validation ofexisting riskassessmentalgorithmBiancari 2006 59 EUROSTAR October 1996–March 2005✓Boult 2007 60,92Australian nationalaudit1 November1999–16 May2001✓✓Brewster 2006 61 MGH a 7 January 1994–31December 2005✓Brown (EVAR EVAR trial 1 andtrial participants) EVAR trial 22007 23September 1999–August 2004✓✓Bush 2007 62 NSQIP b 1 May 2001–31December 2004Buth 2000 63 EUROSTAR January 1994–July1999Buth 2000 64 EUROSTAR January 1994–March 1999Buth 2002 65 EUROSTAR June 1996–March2001✓✓✓✓Buth 2003 66 EUROSTAR Not reported ✓Cuypers 2000 67 EUROSTAR January 1994–July1999Diehm 2007 68 EUROSTAR December 1996–November 2005Diehm 2007 91 EUROSTAR March 1994–November 2006Hobo 2006 69 EUROSTAR December 1999–December 2004Hobo 2007 70 EUROSTAR October 1996–January 2006✓✓✓✓✓Lange 2005 71 EUROSTAR 1996–2004 ✓Leurs 2007 72 EUROSTAR Patients registeredpost 1999includedLeurs 2004 73 EUROSTAR 6-year period toApril 2004Leurs 2006 74 EUROSTAR Recruitmentbegan October1996Leurs 2005 75 EUROSTAR May 1994–December 2003✓✓✓✓continued15© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessTABLE 2 Overview of risk modelling studies (continued)Type of studyStudy details Data source Study datesDevelopmentof a riskassessmentalgorithmLeurs 2005 76 EUROSTAR 1994–2004 ✓Investigationof specific riskfactorsEvaluation/validation ofexisting riskassessmentalgorithmLeurs 2006 77 EUROSTAR Enrolled 1December 1996✓Lifeline Registryof EndovascularAneurysm Repair2002 78US LifelineRegistryNot reported✓Lifeline Registry US Lifelineof Endovascular RegistryAneurysm Repair2005 795-year data fromtrials of four EVARdevices: Ancure,AneuRx, Excluderand Powerlink✓Lottman 2004 80 EUROSTAR January 1994–July2001Mohan 2001 81 EUROSTAR January 1994–January 2000Peppelenbosch EUROSTAR Over 6 years up2004 82 to June 2002Riambau 2001 83 EUROSTAR January 1994–August 1998Ruppert 2006 84 EUROSTAR July 1997–August2004✓✓✓✓✓Sampram 2003 85Cleveland Clinic,OH, USA1996–2002 ✓Timaran 2007 86 NIS c 2001–4 ✓ ✓Torella 2004 87 EUROSTAR May 1994–June2002van Eps 2007 88 EUROSTAR December 1996–January 2005✓✓van Marrewijk EUROSTAR 1996–June 2002 ✓2004 89Zarins 2006 90AneuRx stent grafttrial (40 centres)1998–9 ✓a Massachusetts General Hospital, MA, USA.b National Surgical Quality Improvement Program.c The Nationwide Inpatient Sample from the Healthcare Cost and Utilisation Project.16follow-up of individual patients is generally shorter.Patients are perhaps more ‘typical’ of those inroutine clinical practice. However, many of thestudies begin in the mid-1990s and this raisesissues of older devices and less experience withEVAR.A final caveat is that the majority of the studiesin this section undertook to investigate specificrisk factors using multiple regression analysis. Assuch, statistically significant results can reflect thecovariates used in the model, which often were notclear from the published reports. Furthermore,

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48these studies highlight risk factors but, forexample, do not necessarily quantify the effect ofolder age on risk of aneurysm-related mortality.More useful in this regard were the studies thataimed to develop a risk algorithm 60 or to evaluatean existing algorithm 23,59,86 to aid clinical decisionmaking.These studies were few in number and arediscussed later in this chapter (see Assessment ofrisk factors for adverse outcomes following EVAR).Studies that both develop or validate an algorithmand discuss individual risk factors are discussedwithin each relevant section.Table 3 details the quality of the risk model studies.Collectively the studies described the samples insufficient detail (study characteristics are detailedlater in this chapter; see Assessment of risk factorsfor adverse outcomes following EVAR, especiallyTables 28 and 31). Just over half of the studiesprovided a clear definition of the risk variablesunder investigation, for example the measurementsfor a ‘large’ aneurysm or the definition of ‘old age’.The weaknesses of the studies were in reportingdetails of multivariable modelling, particularlyoutlining the covariates considered to build themodel and how these were chosen. Details of anyinvestigations of interactions between variableswere rarely provided. Appropriateness of analysiscould not always be ascertained as it was not alwaysclear how continuous variables were handledor whether there was a sufficient number ofevents to warrant the number of variables underinvestigation in a study. Finally, nine studies didnot present confidence intervals or other measuresof uncertainty, making it difficult to assess theprecision of any effect measures reported. Overall,no studies clearly met all quality criteria, 12 metfive or six of the seven criteria and the remaindermet fewer than five criteria.Assessment of effectivenessfrom RCTsEVAR versus open repair (unruptured)Study characteristicsThe characteristics of the included RCTs aresummarised in Tables 4–7.PatientsFour RCTs compared EVAR with open repairin patients with unruptured AAAs: DREAM 40,41(n = 351), EVAR trial 1 42,43 (n = 1082) and thesmall RCTs of Cuypers et al. 44 (n = 76) and Soulezet al. 45 (n = 40) (Table 4). It should be noted that alater publication of EVAR trial 1 23 reported a largersample size (n = 1252) because patient recruitment© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.had continued until August 2004. However, patientdetails were not provided and therefore data fromthis later analysis have not been used in the mainanalyses in this report nor in Table 4.Patients were predominantly male in all RCTs,the percentage of men ranging from 91% to 98%,reflecting the disease profile. The average age ofpatients ranged from the late 60s to the mid-70s.The four RCTs were relatively homogeneous interms of average aneurysm diameter: 6.5 cm inEVAR trial 1, 6.0 cm in DREAM, 5.4 cm in Cuyperset al. and 5.2 cm in Soulez et al.The RCTs varied in their reporting ofcomorbidities and patient fitness. In all four RCTsthe majority of patients were current or ex-smokers.Across the four trials the prevalence of diabetes was10–16% and of heart disease was 43–68%. Othercomorbidities were reported for two or three RCTs(Table 5).Patient fitness scores were reported for all fourRCTs but different scoring systems were used.The DREAM investigators 40 and Cuypers et al. 44used the ASA classification system; the majority(about two-thirds) of patients in these studies wereclassified as ASA II. EVAR trial 1 did not reportan overall measure of patient fitness in the mainpublications. 42,43 In a later analysis, 23 patients wereclassified as having good, moderate or poor fitnessbased on modified CPI scores. Of 1252 patientsrandomised (including some randomised too latefor the main analysis), 579 (46.2%) were classifiedas having ‘good’, 331 (26.4%) as having ‘moderate’and 338 (27.0%) as having ‘poor’ fitness.InterventionPatients receiving EVAR in these four RCTs wererecruited between September 1996 44 and August2004 (Table 6), although patients recruited to EVARtrial 1 after December 2003 were not includedin the main analysis. 43 They are included in theanalysis by fitness. 23 EVAR trial 1 had the latestclosing date for recruitment but DREAM had themost recent start (November 2000). The timeperiod covered by the Cuypers et al. trial (1996–9)limits its relevance to current clinical practice.Delay between randomisation and procedure wassimilar for the two larger RCTs (median 39 daysin DREAM and 43 days in EVAR trial 1), althoughwaiting time ranged up to 183 days in DREAM.A wide range of different devices was used withinand between trials. In EVAR trial 1 and DREAM,the most commonly used devices were the Zenith(Cook) and Talent (Medtronic) stent grafts.17

Assessment of clinical effectiveness18TABLE 3 Risk model studies quality assessmentConfidenceintervals orother measuresof uncertaintypresentedMore than 10events perincluded variableContinuousvariables handledappropriatelyInteractionsbetween variablesexploredCovariatesconsideredto build themultivariatemodelIncluded riskvariables clearlydefinedStudy sampleadequatelydescribedAuthorBiancari 2006 59 Yes Yes Yes Unclear Unclear Yes YesBoult 2007 60 Yes Yes Yes Not reported Unclear No NoBrewster 2006 61 Yes No Not reported Unclear Unclear No NoBrown 2007 23 Yes Yes Yes Not reported Yes Yes YesBush 2007 62 Yes Yes Not reported Unclear Yes Yes YesButh 2000 63 Yes No Not reported Unclear Unclear Unclear NoButh 2000 64 Yes Yes Yes Not reported Unclear Unclear YesButh 2002 65 Yes Yes Not reported Unclear Yes Yes YesButh 2003 66 No No Not reported Unclear Unclear Yes YesCuypers 2000 67 Yes Yes Yes Unclear Yes No YesDiehm 2007 68 Yes Yes Yes Unclear Yes Yes NoDiehm 2007 91 Yes Yes Yes Unclear Yes Unclear YesHobo 2006 69 Yes No Yes Unclear Unclear Yes NoHobo 2007 70 Yes Yes Not reported Unclear Yes Yes YesLange 2005 71 Yes Yes Yes Unclear Yes Yes YesLeurs 2007 72 Yes No Not reported Unclear Unclear Unclear YesLeurs 2004 73 Yes No Yes Unclear Unclear No YesLeurs 2006 74 Yes Yes Yes Unclear Yes Yes YesLeurs 2005 75 Yes Yes Yes Unclear Unclear Yes YesLeurs 2005 76 Yes Yes Yes Unclear Unclear Unclear Yes

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Confidenceintervals orother measuresof uncertaintypresentedMore than 10events perincluded variableContinuousvariables handledappropriatelyInteractionsbetween variablesexploredCovariatesconsideredto build themultivariatemodelIncluded riskvariables clearlydefinedStudy sampleadequatelydescribedAuthorLeurs 2006 77 Yes No Not reported Unclear Unclear Unclear YesLifeline Registry of EndovascularAneurysm Repair2002 78Yes No Not reported Limited details No Unclear NoLifeline Registry of EndovascularAneurysm Repair2005 79Yes No Yes Not reported Yes Unclear YesLottman 2004 80 Yes Yes Yes Not reported No Yes NoMohan 2001 81 Yes Yes Yes Unclear No Unclear YesPeppelenbosch Yes No Yes Not reported Unclear Unclear Yes2004 82Riambau 2001 83 Yes Yes Not reported Unclear Yes Yes YesRuppert 2006 84 No No Yes Unclear Unclear Yes NoSampram 2003 85 Yes No Not reported Unclear Yes Yes YesTimaran 2007 86 Yes Yes Yes Not reported No Unclear YesTorella 2004 87 Yes Yes Yes Unclear Yes Yes Yesvan Eps 2007 88 Yes No Yes Unclear Unclear No Yesvan Marrewijk Yes Yes Yes Not reported Unclear Yes Yes2004 89Zarins 2006 90 Yes Yes Yes Not reported No Yes No19© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessTABLE 4 Basic characteristics of RCTs of EVAR vs open repair (unruptured aneurysms)Study(mainpublication)Country wherestudy wasperformedNumber of patients randomisedTotal EVAR ComparatorAge ofpopulationGenderAneurysmdiameterDREAM Multinational;Blankensteijn the Netherlands2005 41 and Belgium351 173 178 Mean (SD)70.1 years[EVAR 70.7(6.6), openrepair 69.6(6.8)]Percentagemale (totalpopulation)91.7% (EVAR93.1%, open90.4%)Mean (SD) 6 cm[EVAR 6 (0.9),open repair 6(0.85)]EVAR trial 1 UK 1082 543 539 Mean (SD)EVAR trial74 (6) yearsparticipants[EVAR 74.22005 43 (6.0), openrepair 74.0(6.1)]Cuypers2001 44 Netherlands 76 57 19 Mean 68.5years (EVAR69, openrepair 68).Range: EVAR52–82, openrepair 52–81Soulez2005 45 Canada 40 20 20 Mean (SD)70.5 years[EVAR 70.3(6.4), openrepair 71.2(7.6)]CT, computed tomography.Percentagemale (totalpopulation)91% [EVAR494 (91%),open repair489 (91%)]Percentagemale (totalpopulation)92% [EVAR54/57 (95%),open repair16/19 (84%)]Percentagemale (totalpopulation) 39patients (98%)[EVAR 19/20(95%), openrepair 20/20(100%)]Mean (SD)6.5 cm [EVAR6.5 (0.9), openrepair 6.5 (1.0)].Measurementtool used spiralCT scan orconventional CTcombined withconventionalangiographyMean 5.4 cm(EVAR 5.6, openrepair 5.2).Range: EVAR5.2–8.4 cm,open repair4.0–6.1 cmMean (SD)5.2 cm [EVAR5.31 (0.48),open repair5.09 (1.61)].Measurementtool used spiralCT20Information on the effects of device brand onoutcomes in RCTs is presented later in this chapter(see Analysis by device type). The majority ofpatients received bi-iliac stent grafts under generalanaesthesia, although in DREAM a substantialminority (40%) received regional anaesthesia. 40,41The type of anaesthesia used was not reported inthe main publications of the EVAR trial 1. 42,43ComparatorThe comparator intervention in these fourRCTs was open repair performed undergeneral anaesthesia according to the centre’sstandard procedures. The median time betweenrandomisation and procedure was similar foropen repair and EVAR in EVAR trial 1 and theDREAM trial but the DREAM trial recorded a highmaximum waiting time (260 days; Table 7).Results by outcome30-day mortalityAll four RCTs comparing EVAR with open repair inpatients with unruptured AAAs (DREAM, 41 EVARtrial 1 42 and the studies by Cuypers et al. 44 andSoulez et al. 45 ) reported 30-day operative mortality(Figure 2). Results from a later analysis of EVARtrial 1 based on a larger sample size gave an oddsratio (OR) of 0.38 (95% CI 0.18 to 0.80). 23 Thepooled estimate of effect suggested a significantlylower rate of 30-day mortality in the EVAR group:pooled OR 0.35 (95% CI 0.19 to 0.63).The small Soulez et al. trial 45 did not contributeto this analysis and exclusion of the less relevantdata from the Cuypers et al. trial 44 (i.e. a pooledanalysis including only the DREAM and EVAR trial1) produced an almost identical measure of effect:pooled OR 0.35 (95% CI 0.19 to 0.64) (Figure 3).

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Body massindex (BMI)TABLE 5 Patient characteristics in RCTs of EVAR vs open repair (unruptured aneurysms)Respiratorydisease Fitness scoresStudy(mainpublication) Smoking history Diabetes Heart disease Hypertension Renal diseaseASA I: 81 (23%) [EVAR 37 (21.4%),open repair 44 (24.7%)]; ASA II:232 (66%) [EVAR 122 (70.5%),open repair 110 (61.8%)]; ASA III:38 (10.8%) [EVAR 14 (8.1%), openrepair 24 (13.5%)]; ASA IV: 0Mean (SD)26.5 kg/m 2[EVAR 26.3(3.4), openrepair 26.6(4.1)]81 (23%)[EVAR 48(27.7%),open repair33 (18.5%)]28 (8%) [EVAR13 (7.5%),open repair 15(8.4%)]198 (56.4%)[EVAR 101(58.4%), openrepair 97(54.5%)]154 (43.8%)[EVAR 71(41%), openrepair 83(46.6%)]35 (10%)[EVAR 18(10.4%),open repair17 (9.6%)]DREAM Current smokers 2092005 41 (64.2%), open repairBlankensteijn (59.6%) [EVAR 111Mean (SD)26.4 kg/m 2[EVAR 26.4(4.6), openrepair 26.4(4.4)]98 (55.1%)]Not reported Not reported Not reported Other; reported in reference 23.Analysis by fitness groups was basedon 626 patients randomised to EVARand 626 randomised to open repairup to 31 August 2004. Patients wereclassified as having good, moderateor poor fitness based on modifiedCustomized Probability Index scores.Good fitness 579 (EVAR 301, openrepair 278), moderate fitness 331(EVAR 160, open repair 171), poorfitness 338 (EVAR 164, open repair174), missing fitness 4 (EVAR 1, openrepair 3)463 (43%)[EVAR 234(44%), openrepair 229(43%)]111 (10%)[EVAR 49(9%), openrepair 62(12%)]EVAR trial 1 EVAR trial participants 2005 43 Current smokers 232(21%) [EVAR 115(21%), open repair117 (22%)]; pastsmokers 747 (69%)[EVAR 367 (68%),open repair 380(70%)]; never smoked102 (9%) [EVAR 61(11%), open repair 41(8%)]ASA II: 64% [EVAR 34 (60%), openrepair 15 (79%)]; ASA III: 36% [EVAR23 (40%), open repair 4 (21%)]Not reported 28% [EVAR17 (30%)COPD,open repair4 (21%)COPD]Not reported56% [EVAR31 (54%),open repair 12(63%)]46% [EVARhistory ofcoronary arterydisease 25(44%), openrepair historyof coronaryartery disease10 (53%)]16% [EVAR8 (14%),open repair4 (21%)]Cuypers 2001 44 Current smokers31 (41%) [EVAR 26(46%), open repair 5(26%)]Cardiac status NYHA class 1: 18(45%) [EVAR 10 (50%), open repair8 (40%)]; cardiac status NYHA class2: 22 (55%) [EVAR 10 (50%), openrepair 12 (60%)]9 (22%)[EVAR 6(30%), openrepair 3(15%)]CrCl < 50 ml/min): 6 (15%)[EVAR 1 (5%),open repair 5(25%)]18 (45%)[EVAR 8(40%), openrepair 10(50%)]27 (68%)[EVAR 13(65%), openrepair 14(70%)]BMI > 30 kg/m 2 17 (42%)[EVAR 8(40%), openrepair 9(45%)]6 (15%)[EVAR 1(5%), openrepair 5(25%)]Soulez 2005 45 Current smokers8 (20%) [EVAR 5(25%), open repair 3(15%)]; past smokers27 (68%) [EVAR 14(70%), open repair 13(65%)]; never smoked5 (12%) [EVAR 1(5%), open repair 4(20%)]ASA, American Society of Anesthesiologists; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; NYHA, New York Heart Association.21© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness22TABLE 6 Intervention characteristics in RCTs of EVAR vs open repair (unruptured aneurysms)Graft type(EVAR) AnaesthesiaElective oremergencyprocedure Type of device (EVAR)Time lapse betweenrandomisation andprocedureStudy (mainpublication) Dates of procedureLocal 9 (5.3%);regional 68(39.8%); general94 (54.9%)Uni-iliac 6(3.5%); bi-iliac160 (94%); other(endovasculartube graft) 1(0.6%)Zenith 57 (33.3%); Talent 46(26.9%); Excluder 37 (21.6%); other30 (17.5%)Elective 173 (100%);emergency 0Median 39 days, range1–183 daysDREAM November 2000–DecemberBlankensteijn 20032005 41Not reportedUni-iliac 51(10%) (basedon n = 512);bi-iliac 461(90%) (based onn = 512)Zenith 261 (51%) (based on n = 512;n = 318 in later analysis based onpatients randomised up to August2004); Talent 167 (33%) (based onn = 512; n = 187 in later analysis basedon patients randomised up to August2004); Excluder 36 (7%) (based onn = 512; n = 37 in later analysis basedon patients randomised up to August2004); other (Quantum or Teramed10) (2%) (based on n = 512)Elective 512 (94% ofrandomised patients);emergency 0 (0%)Median 43 days (IQR28–69), range 28–70daysEVAR trial 1 EVAR trial participants 2005 43 September 1999–1 July 2004for main analysis. Additionalpatients recruited up to 31August 2004 included in someanalysesGeneral 57(100%)Bi-iliac 57(100%)Stentor 3 (5%); Vanguard 22 (39%);AneuRx 30 (52%); Lifepath 1 (2%);1 (2%) had open repairNot reported Not reported; probablyelective, no mention ofemergencyCuypers 2001 44 September 1996–October1999Local 1 (5%)EVAR; regional1 (5%) EVAR;general 18(90%) EVARTalent 20 (100%) Bi-iliac 20(100%) EVARpatientsSoulez 2005 45 September 1998–July 2002 Not reported Not reported; probablyelectiveIQR, interquartile range.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 7 Comparator characteristics in RCTs of EVAR vs open repair (unruptured aneurysms)Elective or emergencyprocedure AnaesthesiaTime lapse betweenrandomisation andprocedureOpen repair or nonsurgicalprocedure Dates of procedureStudy (main publication)Elective 178 (100%) Local 1 (0.6%) (crossoverto EVAR); regional 2 (1.1%)(crossovers to EVAR);general 171 (98.3%)(all patients except 3crossovers)Median 39 days, range4–260 daysNovember 2000–December2003DREAMOpen repair. Particular openBlankensteijn 2005 41 technique used was at thediscretion of the surgeonNot reportedElective 496 (92.0% ofrandomised patients);emergency unclear [possibly3 (

Assessment of clinical effectivenessReview:Comparison:Outcome:EVAR meta-analysis01 EVAR vs open repair01 30-day mortalityStudy orsubcategoryEVARn/NOpen repairn/NPeto OR95% ClPeto OR95% ClCuypers 2001 44 1/57 1/19 0.26 (0.01 to 6.49)DREAM 41 2/171 8/174 0.30 (0.08 to 1.04)EVAR I 42 9/532 25/518 0.37 (0.19 to 0.73)Soulez 2005 45 0/20 0/20 Not estimableTotal (95% Cl) 780 731 0.35 (0.19 to 0.63)Total events: 12 (EVAR), 34 (Open repair)Test for heterogeneity: χ 2 = 0.12, df = 2 (p = 0.94), I 2 = 0%Test for overall effect: z = 3.52 (p = 0.0004)FIGURE 2 EVAR vs open repair: meta-analysis of RCTs for 30-day mortality.0.1 0.2 0.5 1 2 5 10Favours treatment Favours controlAbdominal aortic aneurysm-related mortalityThe two small RCTs failed to provide informationon AAA-related mortality at mid-term follow-up.The DREAM trial and EVAR trial 1 had similardefinitions of AAA-related mortality, i.e. deathwithin 30 days of the original procedure or areintervention. DREAM was originally designedto detect differences in a primary end point ofshort-term mortality and complications and so itspower to detect differences at longer-term followupis unclear. The mean duration of mediumtermfollow-up was about 22 months in DREAMcompared with a median of about 35 months (2.9years) in EVAR trial 1. Maximum follow-up inDREAM was 42 months whereas 24% of patients inEVAR trial 1 were followed up for 4 years or more.Longer-term data for AAA-related mortality werenot available.Both RCTs reported lower rates of AAA-relatedmortality in patients treated with EVAR than inthose undergoing open repair. In DREAM, 3/173patients in the EVAR group (2.1%) and 9/178 inthe open repair group (5.7%) died of aneurysmrelatedcauses. The estimated hazard ratio (HR)was 0.27 (95% CI 0.07 to 1.00, p = 0.05). In EVARtrial 1 there were 19/543 and 34/539 deaths in theEVAR and open repair groups respectively. Theunadjusted HR was 0.55 (95% CI 0.31 to 0.96,p = 0.04); HRs adjusted for primary and secondarycovariates were similar. Results from a later analysisof EVAR trial 1 based on a larger sample size gavean HR of 0.60 (95% CI 0.35 to 1.02). 23The pooled estimate for the HR across the twotrials was 0.49 (95% CI 0.29 to 0.83, p = 0.007),confirming a statistically significant benefit ofEVAR over open repair for this outcome (Figure 4).In a post hoc analysis, follow-up was dividedinto the first 6 months after randomisation andthe period beyond 6 months. The HR for theReview:Comparison:Outcome:EVAR meta-analysis01 EVAR vs open repair06 30-day mortality, DREAM and EVAR IStudy orsubcategoryEVARn/NOpen repairn/NPeto OR95% ClPeto OR95% ClDREAM 41 2/171 8/174 0.30 (0.08 to 1.04)EVAR I 42 9/532 25/518 0.37 (0.19 to 0.73)Total (95% Cl) 703 692 0.35 (0.19 to 0.64)Total events: 11 (EVAR), 33 (Open repair)Test for heterogeneity: χ 2 = 0.09, df = 1 (p = 0.77), I 2 = 0%Test for overall effect: z = 3.42 (p = 0.0006)0.1 0.2 0.5 1 2 5 10Favours treatment Favours control24FIGURE 3 EVAR vs open repair: meta-analysis of the DREAM and EVAR trial 1 RCTs for 30-day mortality.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Review:Comparison:Outcome:EVAR meta-analysis01 EVAR vs open repair04 AAA mortalityStudy orsubcategoryEVARn/NOpen repairn/NHazard ratio95% ClHazard ratio95% ClDREAM 41 3/173 9/178 0.27 (0.07 to 1.00)EVAR I 43 19/543 34/539 0.55 (0.31 to 0.97)Total (95% Cl) 716 717 0.49 (0.29 to 0.83)Total events: 22 (EVAR), 43 (Open repair)Test for heterogeneity: χ 2 = 0.95, df = 1 (p = 0.33), I 2 = 0%Test for overall effect: z = 2.68 (p = 0.007)0.1 0.2 0.5 1 2 5 10Favours treatment Favours controlFIGURE 4 EVAR vs open repair: meta-analysis of RCTs for abdominal aortic aneurysm-related mortality at follow-up.first 6 months was 0.42 (95% CI 0.21 to 0.82), astatistically significant difference favouring theEVAR group. For the later period the HR was 1.15(95% CI 0.39 to 3.41), i.e. there was no significantdifference between groups; the wide confidenceinterval reflected the small number of AAA-relateddeaths during this period.All-cause mortalityOf the four relevant RCTs, only DREAM and EVARtrial 1 provided useful information on all-causemortality at follow-up (2 years in DREAM and 4years in EVAR trial 1). The trial by Soulez et al. 45reported only one death during a mean follow-upof 29 months for the EVAR group and 27 monthsfor the open repair group. In the trial by Cuypers etal. 44 patients were only followed up for 30 days.The two main RCTs reported no significantdifferences in medium-term (35 and 42 months,respectively) mortality in patients treated withEVAR compared with those treated with openrepair. In DREAM, 20/173 patients in the EVARgroup and 18/178 in the open repair group diedof any cause. The estimated unadjusted HR was0.94 (95% CI 0.50 to 1.79, p = 0.86). In EVAR trial1 there were 100/543 and 109/539 deaths in theEVAR and open repair groups respectively. Theunadjusted HR was 0.90 (95% CI 0.69 to 1.18,p = 0.46); HRs adjusted for primary and secondarycovariates were similar. Results from a later analysisof EVAR trial 1 based on a larger sample size gavean HR of 0.93 (95% CI 0.74 to 1.18). 23In a post hoc analysis, follow-up was dividedinto the first 6 months after randomisation andthe period beyond 6 months. The HR for thefirst 6 months was 0.55 (95% CI 0.33 to 0.93), astatistically significant difference favouring the© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.EVAR group. For the later period the HR was 1.10(95% CI 0.80 to 1.52), i.e. there was no significantdifference between groups.A pooled analysis of the two trials confirmed thatthere was no statistically significant differencebetween EVAR and open repair for all-causemortality at medium-term follow-up (Figure 5).RuptureThe four included RCTs provided limitedinformation on rupture as a separate outcome.The DREAM study 40,41 reported that there wereno documented postoperative ruptures but thatthere were two sudden deaths following EVAR inwhich the possibility of rupture was consideredbut not proved. There were no aneurysm rupturesin either group in the small short-term study byCuypers et al. 44 In the small study by Soulez et al. 45there was one rupture in a patient treated withEVAR. In EVAR trial 1 43 three patients randomisedto EVAR and seven randomised to open repairhad a rupture before surgery. There were two fatalruptures in the EVAR group and one in the openrepair group within 30 days of surgery. After the30-day point there were six deaths from rupture inthe EVAR group and one in the open repair group.At follow-up, nine patients in the EVAR groupwere reported with graft rupture as a complication,compared with none in the open repair group.These limited data suggest that rupture may bemore of an issue following EVAR than followingopen repair.EndoleakAcross the included RCTs endoleaks occurred atvarying frequencies (up to approximately 20%)following EVAR in those trials reporting this25

Assessment of clinical effectivenessReview:Comparison:Outcome:EVAR meta-analysis01 EVAR vs open repair02 All-cause mortalityStudy orsubcategoryEVARn/NOpen repairn/NHazard ratio95% ClHazard ratio95% ClDREAM 41 20/173 18/178 0.94 (0.50 to 1.79)EVAR I 43 100/543 109/539 0.90 (0.69 to 1.18)Total (95% Cl) 716 717 0.91 (0.71 to 1.16)Total events: 120 (EVAR), 127 (Open repair)Test for heterogeneity: χ 2 = 0.02, df = 1 (p = 0.89), I 2 = 0%Test for overall effect: z = 0.78 (p = 0.44)0.1 0.2 0.5 1 2 5 10Favours treatment Favours controlFIGURE 5 EVAR vs open repair: meta-analysis of RCTs for all-cause mortality at follow-up. (Academic-in-confidence information onEVAR trial 1 has been omitted.)FIGURE 6 Six-year survival curves for all-cause mortality in EVAR trial 1. (Academic-in-confidence information has been removed.)outcome (Table 8). Type II endoleaks were mostcommon, followed by type I. The Cuypers et al.study 44 did not report data on endoleaks and theDREAM study only reported endoleaks requiringreintervention in the perioperative period [two(1.2%), of which one was regarded as a severecomplication]. 40Device migrationOnly the EVAR trial 1 43 reported on devicemigration after EVAR. In this trial, 12/529 patientswith a completed EVAR (2.3%) experienceddevice migration during follow-up, of which sevenrequired reintervention.ReinterventionsThe DREAM and EVAR trial 1 studies comparedoverall reintervention rates between patientstreated with EVAR and those treated with openrepair. In DREAM, 41 the risk of reintervention wassignificantly higher in the EVAR group for the first9 months (HR 2.9, 95% CI 1.1 to 6.2, p = 0.03)but the groups were not significantly differentthereafter (HR 1.1, 95% CI 0.1 to 9.3, p = 0.95).Across the medium-term follow-up in EVAR trial1, 43 the HR for reintervention was 2.7 (95% CI1.8 to 4.1), indicating a significantly higher riskin the EVAR group. The 4-year point estimatesfor reintervention were 20% for the EVAR groupcompared with 6% for the open repair group. 43Specific reinterventions of interest are shownin Table 9. When reported (EVAR trial 1 andSoulez et al.), rates of short-term EVAR-specificreinterventions were similar to rates of reexplorationof open repair. Conversion of EVARTABLE 8 Occurrence of endoleaks in RCTs of EVAR vs open repair (unruptured aneurysms)EndoleakStudy (mainpublication) Type I Type II Type IIIDREAMBlankensteijn2005 41 Not reported Not reported Not reportedEVAR trial 1 27 (17 with reintervention)EVAR trial at follow-up (of 529 EVARparticipants patients with repair completed).2005 43 Unspecified endoleak reported in4 patients (4 with reintervention)79 (17 with reintervention) atfollow-up (of 529 EVAR patientswith repair completed)8 (4 with reintervention) atfollow-up (of 529 EVAR patientswith repair completed)Cuypers 2001 44 Not reported Not reported Not reported26Soulez 2005 45 2 (10%) EVAR 3 (15%) EVAR Not reported

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48to open repair within 30 days occurred in 10/531patients (1.9%) in EVAR trial 1. 42,43 Cuypers et al. 44reported no conversions after EVAR, and the othertwo trials did not report this outcome.Short-term adverse eventsOur analysis of major short-term adverse eventsconcentrated on cardiac and cerebrovascular eventswithin 30 days of surgery. The DREAM, 40,41 EVARtrial 1 42,43 and Soulez et al. 45 RCTs did not reportthis information. DREAM reported complicationsrather than specific events.Of the trials comparing EVAR and open repair inpatients with unruptured AAA, only Cuypers et al. 44reported on cardiac events: three (5%) in the EVARgroup and two (11%) in the open repair group.Health-related quality of lifeAll four RCTs reported some details on HRQoL.All used the Medical Outcomes Study Short Form-36 (SF-36) questionnaire, but different componentswere reported, making it difficult to synthesisescores across studies. Cuypers et al. and EVAR trial1 also used the EuroQoL 5 dimension (EQ-5D)TABLE 9 Reinterventions in RCTs of EVAR vs open repair (unruptured aneurysms)Study (mainpublication)Conversion toopen repair(EVAR grouponly)Correctionof endoleak(EVAR grouponly)DREAM Not reported 2 (1.2%), ofBlankensteijnwhich 1 was2005 41 classed assevere (0.6%)Reexplorationofopen repair(open grouponly)Other(specify)Cumulativerate fromKaplan–MeiercurveHazard ratioNot reported Not reported Not reported 9 months: 2.9(95% CI 1.1 to6.2, p = 0.03)favouring openrepair; > 9months: 1.1(95% CI 0.1 to9.3, p = 0.95)EVAR trial 1 10/531 at 30EVAR trial days (intentionparticipants to treat)2005 4318/531 at 30days (intentionto treat)15/516 at30 days(intention totreat) (16/519patients withopen repaircompleted atfollow-up)Not reported EVAR 20%,open repair6% (4-year pointestimates)2.7 (95% CI1.8 to 4.1)Cuypers 2001 44One patientrandomised toEVAR receivedan urgentopen AAArepair becauseof aneurysmrupture beforereceivingEVAR. Therewere no otherconversions toopen repairNot reported Not reported Not reported Not reported Not reportedSoulez 2005 45 Not reported 4 patients 1 patient –operativetreatment onan emergencybasis withgraft limbthrombosis, 7months aftersurgery© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.Not reported Not reported Not reported27

Assessment of clinical effectivenessmeasure. This summary concentrates on intergroupdifferences.The DREAM 93 and Cuypers et al. 94 RCTs reportedresults for all eight SF-36 domains and EQ-5D. InDREAM, full results for all time points were notreported. The groups had similar quality of life(QoL) scores at baseline. Three weeks after surgerythe open repair group had significantly lowerscores for physical function, social functioning andphysical role limitations than the EVAR group. Thephysical role limitations score in the open repairgroup was still significantly lower than that of theEVAR group at 6 weeks. However, at 12 monthsthe open repair group scored significantly higherthan the EVAR group for physical function, socialfunctioning, emotional role limitations, bodilypain and general health. EQ-5D scores did notdiffer between the groups until 6 months butat 6 and 12 months the open repair group hadsignificantly higher scores than the EVAR group. 93Cuypers et al. 94 assessed QoL at baseline and after1 and 3 months. Groups were similar at baseline.At 1 month the EVAR group had significantlyhigher scores for physical function, physicalrole limitations, vitality and bodily pain, and forthe usual activities element of EQ-5D. All thesedifferences were no longer present at 3 months.Soulez et al. 45 assessed QoL using the SF-36questionnaire at baseline and at 1, 3, 6, 12, 18 and24 months. Results for the eight SF-36 domainswere presented graphically. The authors reportedthat there were no significant differences betweenthe groups at any time point.The EVAR trial 1 RCT 43 reported EQ-5D weightedindex scores and SF-36 physical and mentalcomponent summary scores for baseline, 0–3months, 3–12 months and 12–24 months (Table10). The groups were similar at baseline. The EVARgroup had higher EQ-5D and physical componentsummary scores at 0–3 months but differencesbetween groups were not significant at later timepoints. The mental component summary score didnot differ between groups at any time point. Thenumber of patients evaluated differed between timepoints (Table 10).Overall, these data suggest that there may be ashort-term QoL advantage for patients treated withEVAR relative to those who receive an open repair.Longer-term QoL data, by contrast, tend to favouropen repair. These findings probably reflect theless invasive nature of the intervention in EVARcompared with open repair but also the need forcontinuing surveillance and the higher rates ofcomplications and reinterventions following EVAR.TABLE 10 Summary of health-related quality of life data from the EVAR trial 1 RCTBaseline scores, mean (SD)Study (mainpublication)HRQoLmeasure usedEVARpopulationEVAR trial 1 EQ-5D 0.75 (0.22)participants 2005 43EVAR trial(541 patients)Comparatorpopulation0.74 (0.23)(531 patients)Mean difference between populations atfollow-up0–3 months: crude 0.06 (SE 0.02), adjusted forbaseline score 0.05 (SE 0.02) (482 patients);3–12 months: crude –0.01 (SE 0.02), adjustedfor baseline score –0.01 (SE 0.01) (885 patients);12–24 months: crude –0.01 (SE 0.02), adjustedfor baseline score –0.02 (SE 0.02) (764 patients)SF-36 physicalcomponentsummary39.92 (5.92)(533 patients)39.83 (5.90)(534 patients)0–3 months: crude 1.68 (SE 0.53), adjusted forbaseline score 1.66 (SE 0.50) (462 patients);3–12 months: crude –0.05 (SE 0.40), adjustedfor baseline score 0.04 (SE 0.37) (849 patients);12–24 months: crude –0.16 (SE 0.44), adjustedfor baseline score –0.15 (SE 0.40) (692 patients)SF-36 mentalcomponentsummary43.59 (6.79)(533 patients)43.95 (6.73)(534 patients)0–3 months: crude –0.18 (SE 0.66), adjusted forbaseline score –0.05 (SE 0.66) (462 patients);3–12 months: crude 0.46 (SE 0.46), adjustedfor baseline score 0.41 (SE 0.45) (849 patients);12–24 months: crude –0.22 (SE 0.50), adjustedfor baseline score –0.29 (SE 0.49) (692 patients)28

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48EVAR versus open repair(ruptured aneurysms)Study characteristicsOne RCT 47 compared EVAR and open repair inpatients with ruptured AAAs. Only 32 patients wererandomised compared with a planned sample sizeof 100 and so it is difficult to draw firm conclusionsfrom the trial. Compared with RCTs of electiveEVAR, the patients were similar in age but hadlarger aneurysms and the proportion of womenwas slightly higher. Non-commercial stent graftswere used in patients receiving EVAR. Other studycharacteristics are shown in Tables 11–14.Results30-day mortalityOf the 15 patients randomised to EVAR, one diedbefore receiving surgery, one was converted to openrepair and subsequently died and six died in theperioperative period following EVAR. Thus, onan ITT basis the mortality rate was 8/15 (53%). Of17 patients randomised to open repair, three diedbefore surgery, two died on the operating tableand four died in the perioperative period, givingan ITT mortality rate of 9/17 (53%). Other longertermmortality data were not reported.Adverse eventsIn total, 5/11 EVAR patients (45%) and 7/12open repair patients (58%) who survived theprocedure experienced cardiac events. All eventswere classified as moderate except for one severeevent in the open repair group. One patient inthe EVAR group suffered severe cerebrovascularcomplications, compared with none in the openrepair group. 47EVAR versus non-surgical management(patients with unruptured aneurysmsconsidered unfit for open repair)Study characteristicsEVAR trial 2 46 is the only published RCT in thispatient group. This UK RCT compared EVAR(n = 166) with non-surgical management (n = 172)in patients judged to be unfit for open repair.The trial met all quality criteria. The primaryend point was all-cause mortality and secondaryend points were aneurysm-related mortality,HRQoL, postoperative complications and hospitalcosts. A total of 14 patients randomised toEVAR died before operation (including six fromAAA rupture), and 47 patients assigned to nonsurgicalmanagement received surgical aneurysmrepair (including 12 who received open repairdespite having been classified as unfit for thisprocedure). These factors complicate the analysisand interpretation of the trial. Tables 15–18 givedetails of patient, intervention and comparatorcharacteristics.Results30-day mortalityShort-term mortality is not a meaningful outcomefor comparing between EVAR and no surgicalintervention. In the EVAR group of EVAR trial 2, 4613/150 patients who had the procedure (9%) diedwithin 30 days. Of the 47 patients randomised tonon-surgical treatment who crossed over to receiveEVAR or open surgery, one (2%) died within 30days.AAA-related mortalityIn the EVAR trial 2 RCT there was no significantdifference in AAA-related mortality betweenTABLE 11 Basic characteristics of the RCT for EVAR vs open repair in ruptured aneurysmStudy(mainpublication)CountryNumber of patients randomisedTotal EVAR ComparatorAge ofpopulationGenderAneurysmdiameterHinchliffe2006 47UK, UniversityHospitalNottingham32 15 17 Median:EVAR 74years (IQR68.8–79.5);open repair80 years(IQR 73.8–83.8)Male (totalpopulation)75% (24/32)Median 8.5 cm(IQR 8.0–10.0)in patients whohad EVAR.Measurementtool used CTscanCT, computed tomography; IQR, interquartile range.29© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness30TABLE 12 Patient characteristics in the RCT for EVAR vs open repair in ruptured aneurysmBody massindex (BMI)Respiratorydisease Fitness scoresStudy (mainpublication) Smoking history Diabetes Heart disease Hypertension Renal diseaseNot reportedNot reported;not applicableto this patientpopulation3/32 (9%) 3/32 (9%)with chronicobstructiveairways diseaseNot reported 8/32 (25%) 13/32 (41%);measurementtool not reportedHinchliffe 2006 47 Current smokers10/32 (31%), pastsmokers 11/32(34%), neversmoked 11/32(34%)TABLE 13 Intervention characteristics in the RCT for EVAR vs open repair in ruptured aneurysmType of device(EVAR) Graft type (EVAR) AnaesthesiaElective oremergencyprocedureTime lapse betweenrandomisation andprocedureStudy (mainpublication) Dates of procedureGeneral 13 (100%)Uni-iliac 11 (100%)(of 13 patients whounderwent EVAR,1 was converted toopen repair and 1 toaxillobifemoral graft)All patients received atwo-piece aorto-uniiliacstent graft madewith Gianturco stentswith an uncoveredsuprarenal componentEmergency 13 (100%)(13/15 randomisedpatients underwentEVAR)Median time fromclinical diagnosis tooperation: 75 minutes(IQR 64–126)Hinchliffe 2006 47 1 September 2002–31December 2004IQR, interquartile range.TABLE 14 Comparator characteristics in the RCT for EVAR vs open repair in ruptured aneurysmElective or emergencyprocedure AnaesthesiaTime lapse betweenrandomisation andprocedureOpen repair or nonsurgicalprocedure Dates of procedureStudy (main publication)General 15 (100%)Emergency 15 (100%)(14/17 randomised patientsunderwent open repair andone patient crossed overfrom the EVAR group)Median time from clinicaldiagnosis to operation: 100minutes (IQR 46–138)Hinchliffe 2006 47 Open repair 1 September 2002–31December 2004IQR, interquartile range.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 15 Basic characteristics of the EVAR trial 2 RCTNumber of patientsrandomisedAge of population Gender Aneurysm diameterTotal EVAR ComparatorStudy (mainpublication) CountryMedian: EVAR 6.4 cm, non-surgicaltreatment 6.3 cm; range: EVAR6.0–7.4 cm, non-surgical treatment6.0–7.0 cm. Measurement tool usedCT scanPercentage male (total population)288 (85%) (based on n = 339); EVAR141 (85%), non-surgical treatment147 (85%); based on n = 143: Zenithdevice 98/109 (89.9%), Talent 28/34(82.4%)EVAR trial 2 EVAR trialparticipants2005 46 UK 338 166 172 Mean (SD) 76.4 (6.45) years (basedon n = 338); EVAR 76.8 (6.2), nonsurgicaltreatment 76.0 (6.7); basedon n = 143: Zenith device 77.3 (6.8),Talent 75.4 (6.1)CT, computed tomography.TABLE 16 Patient characteristics in EVAR trial 2Respiratorydisease Fitness scores Body mass index (BMI)RenaldiseaseHeartdisease HypertensionStudy (mainpublication) Smoking history DiabetesMean (SD) 26.35 kg/m 2(based on n = 339); EVAR26.4 (SD 4.9), non-surgicaltreatment 26.3 (SD 4.4);based on n = 143: 26.85,Zenith 26.9 (SD 5.0), Talent26.8 (SD 4.6)Not reported Other; reported in reference 23.Fitness scores were assigned topatients randomised up to August2004 (c.f. EVAR trial 1). Mean CPIfitness score 10.0 (SD 11.3) for404 patients (197 EVAR and 207no intervention). Little differencebetween randomised groups (detailsnot reported). Comparison of fitness –179 patients underwent elective AAArepair in EVAR group and 60 patientsin no intervention group: Student’st-test: EVAR 10.5 (SD 11.8); nointervention 6.3 (9.6); p = 0.014Not reported Notreported47 (14%) 233(69%)EVAR trial 2 EVAR trial participants 2005 46 Current smokers:57 (17%); EVAR 29(17%), non-surgicaltreatment 28 (16%)Past smokers: 259(77%); EVAR 127(77%), non-surgicaltreatment 132 (77%)Never smoked:22 (6%); EVAR 10(6%), non-surgicaltreatment 12 (7%)CPI, Customized Probability Index.31© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness32TABLE 17 Intervention characteristics in EVAR trial 2Elective oremergencyprocedure Type of device (EVAR) Graft type (EVAR) AnaesthesiaTime lapse betweenrandomisation andprocedureStudy (mainpublication) Dates of procedureLocal: not explicitlyreported in mainpublication; 66 (46%)based on n = 143 inlater analysis based onpatients randomisedup to August 2004; 49using Zenith device and17 using Talent device.General: 83/150 (55%);73 (51%) based onn = 143 in later analysisbased on patientsrandomised up toAugust 2004; 59 usingZenith device and 14using Talent device; 27(16%) (47 crossovers)Uni-iliac 14 (10%)based on n = 143 inlater analysis based onpatients randomisedup to August 2004; 7using Zenith device and7 using Talent device.Bi-iliac 131 (87%) basedon n = 150; 127 (89%)based on n = 143 inlater analysis based onpatients randomised upto August 2004; 102using Zenith device and25 using Talent deviceNot reported Zenith 86 (59%) (based onn = 150) (n = 109 in later analysisbased on patients randomised upto August 2004); Talent 31/150(21%) (n = 34 in later analysisbased on patients randomisedup to August 2004); Excluder10/150 (7%); other: 9/150 (6%)AneuRx (Medtronic), 5/150 (3%)Quantum (Cordis, Johnson &Johnson, Waterloo, Belgium),2/150 (1%) Bard device (Bard,New Jersey), 1/150 (< 1%) AnsonAorfix (Lambard Medical, Oxford,UK), 1/150 (< 1%) EVT (Guidant,Indianapolis), 1/150 (< 1%)Edwards Lifepath (EdwardsLifesciences, Switzerland)Median: 57 days (IQR39–82) 150 patientsrandomised to EVAR;163 days (IQR 78–477)47 patients crossedover from non-surgicaltreatment group (35had EVAR, 12 had openrepair)EVAR trial 2 EVAR trial participants 2005 46 September 1999–31December 2003 (August2004 for extra patientsincluded in some of theanalyses)IQR, interquartile range.TABLE 18 Comparator characteristics in EVAR trial 2Elective or emergencyprocedure AnaesthesiaTime lapse betweenrandomisation andprocedureOpen repair or nonsurgicalprocedure Dates of procedureStudy (main publication)Not applicable Not applicable Not applicableEVAR trial 2EVAR trial participants2005 46 Non-surgical procedure September 1999–31December 2003 (August2004 for extra patientsincluded in some analyses)

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48FIGURE 7 Six-year survival curves for all-cause mortality EVAR trial 2. (Academic-in-confidence information has been removed.)patients randomised to EVAR and thoserandomised to non-surgical management. Onan ITT basis, 20/166 patients in the EVAR groupand 22/172 in the non-surgical managementgroup died of AAA-related causes by 4 years afterrandomisation, giving a crude HR of 1.01 (95% CI0.55 to 1.84, p = 0.98); HRs adjusted for primaryand secondary covariates were similar. 46All-cause mortalityThere was no significant difference in all-causemortality between patients randomised toEVAR and those randomised to non-surgicalmanagement. Four years after randomisation,overall mortality was 64%. On an ITT basis, 74/166patients in the EVAR group and 68/172 in the nonsurgicalmanagement group died, giving a crudeHR of 1.21 (95% CI 0.87 to 1.69, p = 0.25); HRsadjusted for primary and secondary covariates weresimilar. 46(Academic-in-confidence information has beenremoved.)RuptureIn EVAR trial 2, 46 nine patients randomised toEVAR had a rupture of their AAA before receivingelective treatment. Of those who received EVAR(178 including patients crossing over from thenon-surgical management group), one had a graftrupture following successful treatment. Therewere 23 ruptures in the non-surgical managementgroup, representing 13.4% of the 172 patientsoriginally randomised to this group. The cruderupture rate was nine per 100 person-years.The authors noted that this rupture rate wasconsiderably lower than that reported in otherprospective studies monitoring large aneurysmrupture.EndoleakDetails of endoleaks in patients who received EVARin the EVAR trial 2 RCT are shown in Table 19.These figures refer to all patients treated, includingthose who crossed over from the non-surgicalmanagement group.Device migrationThe number of patients with device migration inEVAR trial 2 was 2/178 patients who received EVAR(including crossovers) (1.1%). This was not an ITTanalysis.ReinterventionsEVAR trial 2 reported that 14/178 patients (7.9%)who received EVAR (including crossovers) requiredreintervention for endoleak, and 8/178 (4.5%)required ‘other surgery’ (unspecified). 46 Theoverall reintervention rate during follow-up was11.5 per 100 person-years for EVAR and 1.8 per100 person-years for non-surgical management.By 4 years the estimated reintervention rates were26% and 4% respectively (HR 5.8, 95% CI 2.4 to14.0, p < 0.0001). 46 This was an ITT analysis andso the reinterventions in the comparator groupmay represent patients who crossed over to surgicaltreatment.The authors noted that the rate of reinterventionsin the EVAR group of EVAR trial 2 seemed higherthan that observed in the EVAR group of EVARtrial 1 (11.5 vs 6.9 per 100 person-years) but thedifference was not statistically significant (HR 1.4,95% CI 0.9 to 2.1, p = 0.1). 46Short-term adverse eventsEVAR trial 2 did not report on cardiac andcerebrovascular events within 30 days of surgery. 46Health-related quality of lifeEVAR trial 2 46 reported the same QoL outcomesas EVAR trial 1. The only statistically significantdifference between groups (p = 0.04), for the SF-36physical component summary score at 0–3 months,favoured the non-surgical management group(Table 20).TABLE 19 Occurrence of endoleaks in the EVAR trial 2 RCTEndoleakStudy (main publication)EVAR trial 2EVAR trial participants 2005 46Type I Type II Type III11/178 patients whoreceived EVAR – not ITT (10complications after EVAR)23/178 patients whoreceived EVAR – not ITT (17complications after EVAR)6/178 patients whoreceived EVAR – not ITT (5complications after EVAR)ITT, intention to treat.33© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessTABLE 20 Summary of health-related quality of life (HRQoL) data from the EVAR trial 2 RCTBaseline scores, mean (SD)Study (mainpublication)HRQoLmeasure usedEVARpopulationComparatorpopulationMean difference between populations atfollow-upEVAR trial 2 EQ-5D weightedEVAR trial index scoreparticipants2005 460.58 (0.31)(164 patients)0.63 (0.28)(171 patients)0–3 months: crude 0.01 (SE 0.05), adjusted forbaseline score 0.03 (SE 0.05) (139 patients); 3–12months: crude 0.04 (0.03), adjusted for baselinescore 0.06 (0.03) (241 patients); 12–24 months:crude 0.05 (0.04), adjusted for baseline score 0.04(0.04) (156 patients)0–3 months: crude –1.64 (1.00), adjusted forbaseline score –1.86 (0.88) (134 patients); 3–12months: crude –0.78 (0.83), adjusted for baselinescore –1.11 (0.77) (224 patients); 12–24 months:crude –1.47 (1.12), adjusted for baseline score –0.64(1.04) (130 patients)0–3 months: crude 1.73 (1.47), adjusted for baselinescore 2.30 (1.38) (134 patients); 3–12 months: crude–0.08 (1.00), adjusted for baseline score 0.94 (0.95)(224 patients); 12–24 months: crude –0.70 (1.32),adjusted for baseline score 0.50 (1.29) (130 patients)SF-36 physicalcomponentsummary35.47 (6.63)(160 patients)35.12 (6.23)(171 patients)SF-36 mentalcomponentsummary45.13 (7.92)(160 patients)46.31 (6.97)(171 patients)34Analysis by device typeA secondary publication from the EVAR trialparticipants 95 reported an analysis by device type ofdata from the EVAR trial 1 and EVAR trial 2 RCTs.This analysis compared rates of reintervention,aneurysm-related mortality and all-cause mortalityin patients who received the Zenith and Talentstent grafts.In EVAR trial 1 the number of reinterventions per100 person-years was 6.4 for Zenith (n = 318) and8.6 for Talent (n = 187); there were 0.8 aneurysmrelateddeaths per 100 person-years for Zenith and1.0 per 100 person-years for Talent; and deathsfrom all causes were 5.9 per 100 person-years forZenith and 8.6 per 100 person-years for Talent.Statistically there were no significant differencesbetween outcomes with the Zenith and Talentdevices. Adjusted HRs were 0.79 (95% CI 0.51 to1.21) for reintervention, 0.88 (95% CI 0.29 to 2.65)for aneurysm-related mortality and 0.79 (95% CI0.53 to 1.19) for all-cause mortality.In EVAR trial 2 the number of reinterventions per100 person-years was 9.6 for Zenith (n = 109) and15.1 for Talent (n = 34); there were 2.8 aneurysmrelateddeaths per 100 person-years for Zenith and4.0 per 100 person-years for Talent; and deathsfrom all causes were 18.5 per 100 person-years forZenith and 23.9 per 100 person-years for Talent.Statistically there were no significant differencesbetween outcomes with the Zenith and Talentdevices. Adjusted HRs were 0.69 (95% CI 0.29 to1.62) for reintervention, 0.94 (95% CI 0.21 to 4.27)for aneurysm-related mortality and 0.85 (95% CI0.45 to 1.60) for all-cause mortality.The DREAM 41 and Cuypers et al. 44 studies didnot report an analysis by device type, and in theHinchliffe et al. 47 and Soulez et al. 45 studies allEVAR procedures involved the same type of device.Analysis by neck angulationNone of the included RCTs reported data allowingan analysis of outcomes by neck angulation.Assessment of effectivenessfrom registriesStudy characteristicsThe study characteristics are summarised in Tables21–24. NVD and RETA included fewer centres andcases than EUROSTAR (4545 cases from 59 centresfor NVD, 1000 cases from 41 centres for RETA,and 8345 from 177 centres for EUROSTAR; Table21) and only involved centres from the UK.Clinical expertiseNVD and RETA did not specify entry requirementsfor centres to be eligible for inclusion in theregistries. It is therefore unclear what level ofexpertise the surgical teams had with performingEVAR and open repair, which makes it difficultto compare patient outcomes for the different

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 21 Overview of included registriesNumber ofpatients treatedDates ofprocedure Type of deviceRegistryname Centre entry criteria Patient entry criteriaStudyRegistered 1999–31 March 2004Not applicableNVD Not reported Suitable for open repair Open infrarenalaortic aneurysmsurgery: 4545cases from 59centresAshley 2005 16Open repair8345 cases from177 EuropeancentresMinimum age 21 years. Patients with aorticaneurysms < 3 cm with iliac aneurysms,pseudoaneurysms or previous (conventional/endovascular) grafts were excluded. Aorticaneurysms measuring 3–4 cm included ifthey were associated with iliac aneurysms.Anatomic configuration suitable for stentedtube or bifurcated prosthesis: infrarenalneck length ≥ 1.5 cm and width < 2.5 cm;iliac artery angulation < 90 degrees (orcorrectable angulation); common iliac artery< 1.2 cm in diameter and non-stenotic(> 0.6 cm diameter after balloon dilatation, ifnecessary). Elective AAA operation, withoutsymptoms of rupture or expansionEUROSTAR Sufficient expertise incentre (involvementin a series of atleast 10 stent graftprocedures for AAA).Throughput of at least10 patients per yearand patients managedby collaboratingvascular surgeonsand internationalradiologistsNot reported.Data collectedprospectively upto June 2006. Datarelating to ‘older’devices excludedfrom the reportZenith 3290/8304 (39.6%);Talent 2349/8304 (28.3%);Excluder 1155/8304 (13.9%);other: AneuRx 984/8304 (11.8%),Endologix 161/8304 (1.9%),Lifepath 134/8304 (1.6%),Fortron 92/8304 (1.1%), EVT73/8304 (0.9%), Anaconda66/8304 (0.8%)EUROSTARcollaborators2006 54EVAR1000 cases from41 centresAge limitations not reported. Aneurysmsize not reported. Suitable for open repair;patients classified as fit or unfit for openrepair were included. Suitable for EVAR;no criteria specified for elective repair,but majority of cases were asymptomatic(83.2%) or symptomatic (13.5%) AAA. Nocriteria specified for emergency repair, butsmall numbers of cases were repair of acutenon-ruptured (1.6%) or stable ruptured(1.4%)RETA Not reported.UK membersof the VascularSurgical Societyand British Societyof InterventionalRadiology registeredcases on a voluntarybasisJanuary 1996–March 2000Zenith 144 (14.4%); Talent 117(11.7%); Excluder 19 (1.9%);other: Ancure 60 (6%), AneuRx254 (25.4%), Bard device 11(1.1%), Baxter device 1 (0.1%),Gianturco-Dacron 123 (12.3%),Gianturco-PTFE 17 (1.7%), HolB Endostent 1 (0.1%), Ivanchev-Malmo 2 (0.2%), Palmaz/PTFE64 (6.4%), Stenford 2 (0.2%),Vanguard 174 (17.4%), missing 11(1.1%)Thomas2005; 56additional datafrom undatedVascularSurgicalSocietyreport 57 andThomas2001 58EVAR35© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness36registries and to ascertain whether there may bean association between surgical experience andoutcomes. Because procedures carried out byspecialist teams with a high level of experiencein EVAR result in lower mortality rates andfewer adverse events that lead to secondaryinterventions, 53 EUROSTAR specifies that centresmust have a throughput of at least 10 patientsundergoing stent graft procedures for AAA peryear if they are to be included in the registry.Data collectionEUROSTAR data were collected using a case recordform, which included an informed consent formfor signing by the patient. Only surgeons fromparticipating centres who had sufficient expertise(i.e. involvement in a series of at least 10 stent graftprocedures for AAA) submitted data to the registry.Submission of data to the NVD was on a voluntarybasis, with almost half of the members of theVascular Society contributing to the databaseat the time of the report. However, to gain atrue picture of the outcomes of vascular surgery(e.g. AAA repair) throughout Great Britain andIreland, inclusion of all surgeons performingsuch operations is needed, but at the time of thereport external validation to ensure accuracy andcompleteness of data had not been undertaken. 16Data collection for RETA was also on a voluntarybasis and the UK centres submitted cases asthey were performed. However, the majority ofendovascular repairs in the UK at the time wereperformed as part of the EVAR trials and casessubmitted to RETA at the time of their report werecases performed outside the trial (usually earlyon in a centre’s experience to allow entry into theEVAR trials), and as such the full RETA data set ofall cases submitted was less representative of UKpractice at the time of the report.It is unclear whether all participants undergoingEVAR or open repair were included in the registry,but as only certain surgeons were submitting cases,potential sample bias cannot be ruled out.Dates of proceduresPatients were registered and treated between1999 and 31 March 2004 for NVD, up to June2006 for EUROSTAR, and between January 1996and March 2000 for RETA. Data from the RETAregistry are therefore very out of date, whichsuggests that the results may not be relevant tocurrent practice. This highlights the importanceof the data provided by the EUROSTAR registry.The relevance of the data is also reflected in theuse of ‘older’ types of devices by the RETA registry.The latest report from the EUROSTAR registryexplicitly excluded any data relating to ‘older’devices and included only those patients treatedwith the newer generation of endografts in currentuse.Procedure detailsThe report from the EUROSTAR registry identifiednine devices, with the Zenith, Talent and Excluderdevices being the main ones in use (39.6%, 28.3%and 13.9%, respectively), all of which are stillin current use. By comparison, the RETA dataincludes 14 devices (four of which were ‘homemade’), the main ones in use being AneuRx, Zenithand Gianturco-Dacron (home made) (25.4%, 14.4%and 12.3%, respectively). However, as mentionedabove and in Chapter 1 (see Description oftechnology under assessment), many of the devicesincluded in RETA are no longer in current use.‘In-house’ (homemade) uni-iliac stents were oncethe most often used type of graft but have nowbeen superseded by commercially available andCE-marked devices, 56 such as those included in theEUROSTAR registry.Bi-iliac grafts were the most prevalent form of grafttype used by EUROSTAR and RETA (89.8% and70.4%, respectively). This reflects the increasinguse of bi-iliac grafts for EVAR, which appear to besuperseding other types of graft such as the aortictube, the use of which fell because of the numberof distal endoleaks associated with this type ofdevice. 56 This again highlights the importance ofthe EUROSTAR data and its greater relevance tocurrent practice as the RETA registry includes theuse of aortic tube grafts and a smaller percentageof patients received bi-iliac grafts compared withpatients in the EUROSTAR registry.General anaesthesia was reported to be used mostoften by all three registries (Table 22).Patient characteristicsFull details of patient characteristics are given inTables 23 and 24.To be eligible for inclusion in the EUROSTARregistry, patients were required to meet specificentry criteria: age greater than 21 years andpresenting for elective AAA operation withoutsymptoms of rupture or expansion. Patients wereexcluded if their aneurysms measured < 3 cm,and patients with aneurysms measuring 3–4 cmwere only included if they were associated with

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 22 Procedure details for included registriesStudy Graft type a Anaesthesia aAshley 2005 16NVDNot applicableBi-iliac 7497/8345 (89.8%); other: straightEUROSTAR2006 54 unknown 131/8345 (1.6%)collaborators 156/8345 (1.9%), tapered 561/8345 (6.7%),Thomas 2005 56RETAUni-iliac 263 (26.4%); bi-iliac 702 (70.4%);other: aortic tube 32 (3.2%), missing data 3Local 1 (0.02%); regional: epidural 34 (0.7%); general2461 (54.1%); general + epidural 1503 (33.1%); total3964 (87.2%); unspecified 546 (12%)Local 515/8345 (6.2%); regional 2091/8345 (25.1%);general 5739/8345 (68.8%)Regional 52/993 (5.2%); general: general alone 908/993(91.4%), general and regional 32/993 (3.2%)a Number of patients (%).iliac aneurysms. The mean aneurysm diameterfor patients included in the registry was 5.84 cm,ranging between 3 and 17.2 cm. The majority ofpatients were male (93.2%) and the mean age was72.5 years, ranging between 34 and 100 years.Approximately half of the patients had a history ofsmoking (51.1%), and a high proportion reporteda history of heart disease (78.8%) and hypertension(65.5%). Almost half had a history of pulmonarydisease (42.3%), a quarter were classed as unfit foropen repair and a quarter were considered obese(Table 24).In the RETA data, details for gender were availablefor only 51.4% of patients; however, 90% of thispopulation was male. The median age reportedwas 73 years, ranging between 44 and 93 years.The health status of patients was unclear fromthe registry data as no details were provided forcomorbidities. However, almost half of patientspresented with aneurysms > 6 cm and fitness scoresindicated that almost a quarter of patients (22.7%)were classified as unfit for open repair. Incompletereporting of details was one of the shortcomingsof this registry as it is difficult to then makecomparisons.In the NVD the majority of patients were male(84.4%), although this figure is almost 10% lessthan the corresponding figure in the EUROSTARpopulation. Mean age was 72.5 years, which wascomparable to that in the EUROSTAR population.The mean aneurysm diameter was not reported butsizes ranged from < 5 cm to > 9.9 cm and there wasa 1-cm difference between the majority of rupturedand the majority of unruptured AAAs. Only onepatient characteristic of interest was reported,which indicated that almost half the population(44.2%) had a history of heart disease.Mortality outcomesMortality data from the three registries aresummarised in Table 25. From the studycharacteristics it can be seen that EUROSTARprovides the most up-to-date and complete sourceof data on EVAR.EUROSTAR 54EUROSTAR presented outcomes for short-term(30-day) and long-term (96 months/8 years)mortality, with 190 (2.3%) deaths occurringwithin 30 days and 789 (9.5%) during the followupperiod. It is unclear from the report whetherpatients died from aneurysm-related or othercauses. Kaplan–Meier survival analysis reportedthe cumulative number of deaths as 979 and amortality rate of 39%. It should be noted, however,that for the 30-day outcome 4543 patients wereobserved out of 5515 expected; 90 patients wereobserved out of 326 expected for 84 months’follow-up; and only 20 patients were observedout of 77 for 96 months’ follow-up. In total, 111patients (1.3%) were lost to follow-up, but thiswill have been included as censored data andaccounted for by the Kaplan–Meier survivalanalysis.RETA 56RETA reported outcomes for short-term (30-day)mortality, 58 aneurysm-related mortality at followupand all-cause mortality at follow-up (5 years/60months) 56 (return rates for follow-up data arereported in Table 25). In total, 58 patients (5.8%)died within 30 days and 9 patients were reportedto have died from fatal rupture (aneurysm-relatedmortality) at follow-up [6 (0.8%) at 1 year and 3(0.8%) at 2 years]. A cumulative rate of all-causemortality was not reported, although figureswere presented for each year of follow-up: 11.9%37© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 24 Patient characteristics for included registries (continued)Respiratorydisease Fitness scores BMIRenaldysfunctionStudy Smoking history Diabetes Heart disease Hypertension2011 patients Not reported Not reported Not reported Not reported Not(44.2%) a reportedNot reported NotreportedAshley 2005 16NVDASA I 635/8288 (7.7%); 2186/8248ASA II 3467/8288 (26.5%)(41.8%); ASA III considered3643/8288 (44%); ASA obeseIV 543/8288 (7%); e2037/8345 (24.4%) f3419/8079(42.3%) (SVS/ISCVS risk score1–3)1155/8066(14.3%); b252/80665337/8142(65.5%) (SVS/ISCVS riskscore 1–3)Cardiac:4957/8141(60.9%) (SVS/ISCVS risk score1–3); carotid:1436/8038(17.9%) (SVS/ISCVS risk score1–3)1045/8126(12.9%)(3.1%); c131/8066EUROSTAR collaborators 2006 54 Current smokers 1885/8107(23.3%) (SVS/ISCVS risk score2–3)Past smokers 2252/8107 (27.8%)(SVS/ISCVS risk score 1) (nonecurrent, but smoked in last 10years)Never smoked 3970/8107 (49%)(SVS/ISCVS risk score 0) (notobacco use or none for last 10years)(1.6%) d Pulmonary:NotreportedNot reported Not reported Not reported Not reported Not reported: 226/997(22.7%) classified asunfit for open repair;699/997 classified as fitfor open repair (ASAI–III).Not reported NotreportedThomas 2005 56RETAASA, American Society of Anesthesiologists; SVS/ISCVS, Society for Vascular Surgery/International Society for Cardiovascular Surgery.a Cardiac history [myocardial infarction (MI) ≤ 6 months ago; MI > 6 months ago; heart failure ≤ 1 month ago; heart failure > 1 month ago; orthopnoea; angina – controlled/onexertion; angina – uncontrolled/at rest].b Creatinine 1.5–3.0 mg/dl, creatinine clearance 30–50 ml/min (SVS/ISCVS risk score 1).c Creatinine 3.0–6.0 mg/dl, creatinine clearance 15–30 ml/min (SVS/ISCVS risk score 2).d Creatinine > 6.0 ml/dl, creatinine clearance < 15 ml/min or on dialysis or with transplant.e ASA IV indicating that a patient is too frail to justify open repair.f Unfit for open repair when factors other than ASA (e.g. obesity, previous laparotomies) were considered.39© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness40TABLE 25 Follow-up and mortality outcomes in included registriesAneurysm-relatedmortality at follow-up All-cause mortality at follow-upStudy Follow-up 30-day mortalityNot reported Not reportedNot reported Crude mortality: unruptured6.8% (95% CI 5.9 to 7.8%);ruptured 41% (95% CI 37.7to 44.3%); total 14.8% (95%CI 13.7 to 16.0%)Ashley 2005 16NVD190/8345 (2.3%) Not reported 789/8345 (9.5%). Cumulative rate from Kaplan–Meiercurve: number of deaths (cumulative) 979, proportiondeaths 0.390, proportion surviving 0.610, survival SE 0.036EUROSTAR Minimum follow-up 30 days;2006 54 years)collaborators maximum follow-up 96 months (8At 1 year: 86/721 (11.9%), missing 7, at risk 728; a 1–2years: 37/369 (10%), missing 1, at risk 372; 2–3 years:13/162 (8%), at risk 161; 3–4 years: 5/63 (7.9%), at risk 65Published paper reports 11% mortality in year 1 and ratesof 10%, 7%, 10% and 8% at 2, 3, 4 and 5 years postprocedure respectively 5658/992 (5.8%) Fatal rupture at 1 year 6(0.8%); fatal rupture at 2years 3 (0.8%)Minimum follow-up 30 days;maximum follow-up 5 years. Returnrates for requested follow-up data:87% at 1 year, 77% at 2 years, 65%at 3 years, 52% at 4 years, 51% at 5years. Median follow-up 3.1 yearsThomas 2005 56RETAa At end of follow-up period. 57

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 26 Complications in included registriesMajor adverse events (30-dayperiod)Study Rupture Endoleak Device migration ReinterventionsNot reported Not applicable Not applicable Not reported Not reportedAshley 2005 16NVDCardiac events: 272; stroke: cerebral: 57Systemic complications from operationto discharge: pulmonary: 174; renal: 181;total systemic complications: 928Conversion to open repair: 30-day conversion:75 patients (0.9%); follow-up conversion: 102patients (1.2%); total: 177 patients (2.1%)Cumulative rate from Kaplan–Meier curve: totalnumber of reinterventions at 84 months: 749;proportion of secondary interventions: 0.18;proportion of secondary intervention free: 0.82;secondary intervention free SE: 0.013; totalnumber of reinterventions at 96 months: 1606;proportion of death and secondary interventions:0.48; proportion of secondary intervention freesurvival: 0.52 (SE 0.022)30 days: 6; follow-up:148; total: 154Cumulative ratefrom Kaplan–Meiercurve. 30 days:496; follow-up:827; total: 1323Proportionendoleaks: 0.325;proportionendoleak free:0.675 (SE 0.021)EUROSTAR collaborators 2006 54 30 days: 4; follow-up:37; total: 41Cumulative rate fromKaplan–Meier curve at84 months: proportionof ruptures: 0.031;proportion rupture free:0.969 (SE 0.011)Conversion to open repair: immediate outcome: 33/996 (3.3%). Correction of endoleak: some included under ‘conversion to open repair’; totals not clearly reportedCumulative rate from Kaplan–Meier curve. Freedom from reintervention: 87% at 1 year, 77% at 2 years, 70% at 3 years, 65% at 4 years, 62% at 5 years 56 Cardiac events: 42 (4.2%) (myocardialinfarction/arrhythmia/left ventricularfailure 57 ); stroke: 15 (1.5%)(cerebrovascular accident/confusion/paraplegia 57 )Cumulative rate from Kaplan–Meiercurve: 30-day rates: 56 any complication272/976 (27.8%), technical complication55/976 (5.6%), wound complications78/976 (8%), renal failure 40/976(4.1%), colonic ischaemia 6/976 (0.6%),other medical complication 147/976(15.1%)Rupture during deployment: 3 (0.3%) 57 Cumulative rate Kaplan–Meier curve: 2% at 5-year followupAt 30 days: 56 type I: proximal 54, distal 19; type II: 44; type III: 15from Kaplan–Meier Cumulative rate 9 (0.9%) with devicemigration requiringconversion to openrepair (immediateNew cases at 1-yearoutcome)68% at 5 years 56 follow-up 2/56 57from curve. Freedom from endoleak: 88% at 1 year, 80% at 2 years, 76% at 3 years, 71% at 4 years, follow-up 3/631;new cases at 2-yearfollow-up 9/331;new cases at 3-yearfollow-up 0/148;new cases at 4-yearThomas2005 56RETA41© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessmortality in year 1 and 10%, 8% and 7.9% at 2, 3,and 4 years post procedure respectively.NVD 16Mortality rates following open repair were reportedfor the 30-day period only, with an overall crudemortality rate of 14.8% (95% CI 13.7 to 16.0%).Crude mortality rates for ruptured and unrupturedAAAs were 41% (95% CI 37.7 to 44.3%) and 6.8%(95% CI 5.9 to 7.8%) respectively (Table 25).Complications (Table 26)EUROSTAR 54Some form of major adverse event was experiencedby 11.1% of patients, with cardiac, pulmonaryand renal events being the most significant. Bythe end of 96 months’ follow-up only a very smallproportion of patients (0.5%) experienced ruptureand device migration (1.8%), whereas 15.9% ofpatients experienced endoleak. In total, 9% ofpatients required some form of reintervention at 84months, increasing to 19.2% at 96 months.RETA 56RETA reported a very small percentage ofruptures during stent deployment (0.35%) 57 and acumulative rate of 2% at 5 years’ follow-up. 56 A totalof 132 cases of endoleak (13.2%) were reported at30 days, 56 with a cumulative rate of 68% free fromendoleak at 5 years’ follow-up. 56 A small numberof device migrations were reported: 9 (0.9%) at 30days (requiring conversion to open repair) and 14over the 4-year follow-up. 57Conversion to open repair within 30 daysoccurred in 3.3% of cases. Kaplan–Meier totals forcumulative rates of reintervention were not clearlyreported; however, the rate at 5 years’ follow-upwas reported as 62%. 56 This 5-year figure reflects amuch higher reintervention rate than that reportedby EUROSTAR at 8 years’ follow-up (19.2%). Onlysmall numbers of cardiac events and stroke werereported at 30 days (4.2% and 1.5%, respectively 57 ),but overall 27.8% were reported as havingexperienced some form of complication (includingtechnical complications and renal failure 56 ).NVD 16No data were reported in the NVD registry foroccurrence of endoleak and device migrationas these complications cannot occur with openrepair. No data were presented for rupture rates,reintervention rates or major adverse events, whichlimits analysis of the data and prevents comparisonwith the EVAR registries.Resource useDuration of surgery for open repair (NVD)ranged from < 30 minutes to > 359 minutes(approximately 6 hours); for EUROSTAR patientsthe duration of surgery was between 25 and 720minutes (12 hours) and for RETA patients theduration of surgery was from 30 to 540 minutes(9 hours). The majority of surgical procedureslasted between 120 and 149 minutes (21.8%) forNVD patients. By comparison, the mean durationfor EUROSTAR patients was 130 minutes andthe median duration for RETA patients was 150minutes (Table 27).The mean length of stay for NVD cases was 13 daysfor unruptured AAAs and 15.2 days for rupturedAAAs. By comparison, EUROSTAR reported amean of 5.9 days 54 (less than half that of NVDcases), and RETA reported a median of 6 days. 57The number of days in hospital ranged from3 to > 30 for RETA, compared with 0–183 forEUROSTAR (Table 27).HRQoL measures and costs and length of stay forreinterventions were not reported by the registries.Assessment of risk factors foradverse outcomes following EVARStudies evaluating/validating existingrisk assessment algorithmsThe Leiden score was investigated in one study 30but this study had fewer than 500 patients so couldnot be included in the review. The Hardman scorewas also investigated in one risk model study 29 butagain fewer than 500 patients were included. Threestudies 23,59,86 investigated existing risk assessmentalgorithms and included more than 500 patients.Biancari et al. 59 investigated the Glasgow AneurysmScore (GAS). The GAS was calculated from dataentered prospectively according to the formula:Risk score = (age in years) + (7 pointsfor myocardial disease) + (10 points forcerebrovascular disease) + (14 points for renaldisease)The EVAR trial participants 23 used a modifiedCustomized Probability Index (CPI) score. Therange of possible scores was –25 (best) to +57(worst) and points were allotted for ischaemic heartdisease (+13), uncontrolled congestive heart failure(+14), receiving treatment for hypertension (+7),respiratory dysfunction (+7), renal dysfunction(+16), beta-blocker use (–15) and statin use (–10).42

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 27 Resource use in included registriesStudy Length of hospital and ICU stay a Duration of surgeryAshley 2005 16NVDUnruptured: 13 (SE 0.21); ruptured:15.2 (SE 0.55)< 30 minutes: 9/2326 (0.4%); 30–59 minutes: 28 (1.2%);60–89 minutes: 145 (6.2%); 90–119 minutes: 356 (15.3%);120–149 minutes: 506 (21.8%); 150–179 minutes: 456(19.6%); 180–209 minutes: 363 (15.6%); 210–239 minutes:154 (6.6%); 240–269 minutes: 136 (5.8%); 270–299 minutes:65 (2.8%); 300–329 minutes: 41 (1.8%); 330–359 minutes:22 (1%); > 359 minutes: 45 (1.9%); unspecified: 2219EUROSTARcollaborators 2006 54 5.9 (SD 8.1)8169 patients (98 patients withhospital stay < 1 day)Range 0–183 days8065 patients; mean duration 130 (SD 58) minutes; range25–720 minutesThomas 2005 56RETAMedian 6 (range 3 to > 30) 57 Median 150 minutes (range 30–540 minutes) 57a Mean number of days unless otherwise stated.The GAS and unmodified CPI score are similarand have been shown to be good predictors ofimmediate postoperative death following electiveopen repair of AAA.Timaran et al. 86 investigated the CharlsonComorbidity Index (CCI). The CCI is a validatedmeasure for use with administrative data thatcorrelates with in-hospital mortality after surgicalprocedures, including AAA repair. The authors firstvalidated the CCI as an independent predictor ofin-hospital mortality following EVAR; the CCI wasthen used to define four surgical risk groups, with aCCI score of 0 corresponding to the lowest risk and3 to the highest risk.All three studies assessed the relationship betweenrisk score and 30-day operative mortality; theGAS 59 and the CPI 23 were also investigated for theirability to predict longer-term all-cause mortality.Only the CPI was tested for aneurysm-relatedmortality at follow-up.Sample sizes of the three studies ranged from1200 to over 65,500 and the data sources usedwere the EUROSTAR registry, the EVAR trial 1RCT and a large US administrative database (Table28). The EVAR trial participants 23 did not reportdetails of the patients studied; the sample includedsome patients randomised too late for inclusionin the main EVAR 1 trial reports 42,43 but patientcharacteristics were presumably similar to thosereported there. Timaran et al. 86 did not report amean age for their population, although an age© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.distribution was reported. Aneurysm diameter wasnot reported in this study, which makes it difficultto assess whether the population included patientswith AAAs smaller than those generally treated inUK practice.Study resultsDetails of the risk scores used in the three studiesand the results are summarised in Tables 28 and29. One study also assessed other risk factors andresults for these factors are discussed later in thischapter (see Studies investigating specific riskfactors).30-day operative mortalityGAS was found to be an independent predictorof postoperative death. The 30-day mortalityrates were 1.1% for patients with a GAS < 74.4,2.1% for GAS 74.4–83.6 and 5.3% for those with ascore > 83.6. The best cut-off value was a GAS of86.6; 30-day mortality was 1.6% in patients witha score below this value and 6.4% in those with ahigher score. 59 CCI score was also found to be anindependent predictor of in-hospital mortality. 86Mortality increased as CCI score increased (ORper point increase 1.12, 95% CI 1.06 to 1.20) andsimilar results were found in a stratified analysisthat included only elective EVAR cases (Table 29).Fitness level (good, moderate or poor) asdetermined from the modified CPI score did notsignificantly affect the OR for EVAR relative toopen repair for 30-day operative mortality. 2343

Assessment of clinical effectiveness44TABLE 28 Characteristics of risk modelling studies evaluating/validating existing risk algorithmsAneurysmdiameterAge ofpopulation GenderStudy Data source Number of patientsMedian aorticdiameter 5.6 cm(IQR 5.1–6.3 cm).Measurementtool used CT scanand intra-arterialdigital subtractionangiographyPercentagemale (totalpopulation)94.1%Median 72.7 years(IQR 67.3–77.7years)5498 patients: 59.5% co-existing myocardialdisease; 5.7% cerebrovascular disease; 18.2%renal diseaseBiancari 2006 59 Registry – dates enrolled and/or treated: October1996–March 2005Registry – other characteristics: EUROSTAR1833 GAS < 74.4; 1832 GAS 74.4–83.6; 1833 GAS> 83.6Not reported Not reported Not reportedEVAR trial 1: 1252 (626 randomised to EVAR and626 to open repair); EVAR trial 2: 404Trial – name of trial: EVAR trial 1 and EVAR trial 2Brown Trial – dates: patients randomised September(EVAR trial 1999–August 2004participants)2007 23Trial – RCTNot reportedPercentagemale (totalpopulation)82.9%65,502 patients Not reported4.6% aged 50–59years; 24.8%aged 60–69;45.9% aged 70–79; 24.7% aged80 or overTimaran Registry – dates enrolled and/or treated: 2001–42007 86 Registry – other characteristics: the data werefrom the Nationwide Inpatient Sample from theHealthcare Cost and Utilization Project. This isthe largest all-payer inpatient database in the USA.It represents a 20% stratified sample of inpatientadmissions to US academic, community and acutecare hospitals nationwide (approximately 1000hospitals in 35 states)IQR, interquartile range.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 29 Results of risk modelling studies evaluating/validating existing algorithmsRisk factor(s) used in model anddefinitions 30-day mortalityAneurysm-related mortality atfollow-up All-cause mortality at follow-upStudyGlasgow Aneurysm Score (GAS)Multivariate analysis showed thatGAS independently predictedpostoperative death (p < 0.001).ROC curve showed GAS witharea under curve of 0.70 (95%CI 0.66 to 0.74, p < 0.001)for predicting postoperativedeath. Best cut-off value 86.6(sensitivity 56.1%, specificity76.2%, accuracy 75.6%, positivepredictive value 6.4%, negativepredictive value 98.4%)No risk factors investigated Multivariate analysis showed that overallsurvival differed significantly among GAStertiles (i.e. < 74.4, 74.4–83.6, > 83.6)(p < 0.001); 5-year overall survival rate forpatients with GAS > 83.6 = 65.2%Biancari 2006 59 GAS: Risk score = (age in years) + (7points for myocardial disease) + (10points for cerebrovascular disease) + (14points for renal disease). Myocardialdisease refers to previously documentedmyocardial infarction and/or ongoingangina pectoris. Cerebrovascular diseaserefers to all grades of stroke and includestransient ischaemic attack. Renal diseaserefers to a history of acute or chronicrenal failure and/or a creatinine levelabove 133 µmol/l and/or creatinineclearance below 50 ml/min (Society forVascular Surgery/International Society ofCardiovascular Surgery risk score of 1or more)Customized Probability Index (CPI)No significant effect of CPIfitness group on benefit of EVARover open repair in EVAR trial 1Good fitness adjusted OR0.23 (95% CI 0.06 to 0.84,p = 0.027); moderate fitnessadjusted OR 0.70 (95% CI 0.19to 2.56, p = 0.586); poor fitnessadjusted OR 0.29 (95% CI 0.07to 1.17, p = 0.082)p-value for test of interaction foradjusted model = 0.363Mortality rates were 0.9/100 person-yearsfor good fitness, 1.2/100 person-years formoderate fitness and 1.6/100 person-yearsfor poor fitnessThere was no significant effect of fitnessgroup on benefit of EVAR over open repairin EVAR trial 1 (no interaction betweenfitness score and randomised group)Crude HRs: good fitness 0.49 (95% CI0.21 to 1.15, p = 0.100); moderate fitness0.91 (95% CI 0.31 to 2.70, p = 0.862);poor fitness 0.60 (95% CI 0.25 to 1.44,p = 0.254)Adjusted HRs: good fitness 0.49 (95% CI0.21 to 1.16, p = 0.106); moderate fitness1.00 (95% CI 0.33 to 3.00, p = 0.999);poor fitness 0.50 (95% CI 0.21 to 1.23,p = 0.131)p-value for test of interaction for adjustedmodel = 0.371Mortality rates were 5.3/100 person-yearsfor good fitness, 7.7/100 person-years formoderate fitness and 9.9/100 person-yearsfor poor fitnessThere was no significant effect of fitnessgroup on benefit of EVAR over open repairin EVAR trial 1 (no interaction betweenfitness score and randomised group)Crude HRs: good fitness 0.76 (95% CI0.52 to 1.11, p = 0.151); moderate fitness1.11 (95% CI 0.71 to 1.75, p = 0.643);poor fitness 1.02 (95% CI 0.68 to 1.51,p = 0.941)Adjusted HRs: good fitness 0.76 (95% CI0.52 to 1.11, p = 0.151); moderate fitness1.13 (95% CI 0.72 to 1.79, p = 0.595);poor fitness 0.97 (95% CI 0.65 to 1.45,p = 0.873)p-value for test of interaction for adjustedmodel = 0.281continuedBrown (EVAR trial participants) 2007 23 Patients were classified as havinggood, moderate or poor fitness basedon a modified CPI score (based oncardiovascular disease, respiratorydysfunction, renal dysfunction andmedication status). The modification wasthe exclusion of cerebrovascular diseaseand the weighting of severe aorticstenosis and arrhythmia as risk factorssimilar to ischaemic heart disease45© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessAneurysm-related mortality atfollow-up All-cause mortality at follow-up46Risk factor(s) used in model anddefinitions 30-day mortalityStudyNo risk factors investigated No risk factors investigatedTABLE 29 Results of risk modelling studies evaluating/validating existing algorithms (continued)Charlson Comorbidity Index (CCI)From multivariate regressionmodel OR 1.12 (95% CI 1.06 to1.20, p < 0.001)A higher CCI score wasassociated with early death: CCI0: 1.8%; CCI 1: 2.0% CCI 2:2.2%; CCI ≥ 3: 3.7%; p < 0.001Stratified analysis that includedonly elective EVAR found theper point CCI score to be anindependent predictor of inhospitalmortality (OR 1.38, 95%CI 1.29 to 1.47)Timaran 2007 86 The score is a validated measure for usewith administrative data that correlateswith in-hospital morbidity and mortalityafter surgical procedures (includingelective AAA repairs). Each of theindicated diagnoses is assigned a weightand summed to provide a patient’s totalscore [from 0 (low risk) to > 3 (highrisk)]ROC, receiver operating characteristic.

Assessment of clinical effectivenessTABLE 30 Survival at 3 and 5 years after EVAR predicted by ASA score, age and aneurysm sizeAdditional detailsAge (years)70 77 83Predicted survivalat 3 yearsPredicted survivalat 5 yearsASAMax.diameter(cm)Creatinine (μmol/l)85 125 85 125 85 125ASA II 5 91% 88% 87% 84% 83% 79%5.8 89% 87% 86% 82% 81% 77%7.4 87% 83% 82% 77% 77% 71%ASA III 5 86% 82% 81% 76% 75% 69%5.8 84% 80% 78% 73% 72% 66%7.4 80% 75% 73% 67% 66% 59%ASA IV 5 79% 74% 72% 65% 64% 56%5.8 76% 71% 69% 62% 60% 52%7.4 71% 64% 62% 54% 53% 44%ASA II 5 85% 81% 79% 74% 74% 68%5.8 83% 79% 77% 72% 71% 54%7.4 79% 74% 72% 65% 64% 57%ASA III 5 77% 72% 70% 63% 62% 54%5.8 75% 69% 67% 60% 58% 50%7.4 69% 62% 60% 52% 50% 41%ASA IV 5 67% 60% 57% 49% 48% 39%5.8 64% 56% 53% 45% 43% 34%7.4 56% 48% 45% 36% 34% 25%Shading indicates estimates with low certainty. Sample sizes < 10 in these regions.Reprinted from Boult et al., 60 with permission from the European Society for Endovascular Surgery.48logistic regression models bootstrapping was usedto assess the internal model validity.All outcome models had a reasonable fit with theexception of the outcome model for conversionto open repair. In terms of validation, survival,aneurysm-related deaths, migrations andconversions to open repair performed best inpredictive discrimination. Models for survival,migrations and conversions to open repairperformed best in terms of bias-correctedR-squared index. The models with the smallestcalibration error were 3- and 5-year survival,early deaths and mid-term type 1 endoleaks.The interactive model is available from www.surgeons.org/asernip-s/audit.htm. Users can enterup to eight preoperative variables and review thepredicted success rate and confidence intervals.The model can be used at an initial consultationwhere, for example, information is known aboutage, ASA score, aneurysm diameter, genderand serum creatinine. Following CT scanning,measurements could be added on aortic neckangle, infrarenal neck length and infrarenal neckdiameter.Studies investigating specific risk factorsIn total, 32 studies investigated specific riskfactors after EVAR. 60–91 One study 60 has alreadybeen discussed above as its main aim was todevelop a risk algorithm. However, specific riskfactors were also discussed and are reported here.Of the three studies discussed in the section onvalidation of existing algorithms, 23,59,86 one 86 alsopresents further data on specific risk factors andis mentioned in this section. The remaining 30studies focused exclusively on the evaluation of oneor more risk factors after EVAR. Table 31 details

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48the characteristics of patients in all of the studiesincluded in this section.Sample size ranged from 676 to 65,502. Sixstudies 60,61,73,85,90,91 had fewer than 1000 participants,25 62–72,74–84,87–89 had between 1000 and 6500participants and one US study had over 65,000participants. 86 The mean or median age of between70 and 75 years of age reflected the fact that AAAis predominantly a disease of old age. Equally, thehigher prevalence of AAAs in men was reflected inthe studies with percentages of men ranging from81.4% to 99.3% when reported. When reported,mean aneurysm size tended to be between 5.5 cmand 5.9 cm. However, not all studies reported therange of aneurysm size and it is likely that somestudies contained participants receiving EVARwho would not normally be considered given theiraneurysm size under UK current practice.Across the studies the following risk variables wereinvestigated: age, gender, smoking status, ASAstatus, pre-existing conditions, renal function,fitness for open procedure, aneurysm size, aorticneck and aneurysm angle, aortic neck length andgraft configuration and device type. Each riskvariable will be discussed in its own section andeach of the five outcomes of 30-day mortality,aneurysm-related mortality, all-cause mortality,reintervention and endoleak will be discussed byvariable. All studies contributing relevant data toeach section will be discussed as appropriate.Some studies presented ORs or HRs whereasothers reported a variable as significant or notsignificant. Details of any numerical data providedcan be found for each individual study in Appendix4. Included in each section on a given risk variableis a graphical representation of the evidence. Theheight of the bars represents sample size and thedata source is indicated by the shading of the bars.From this it can be determined which variablesfrom which studies and for which outcomes havebeen found in multivariable regression to besignificant or non-significant. It should, however,be noted that studies may be missing on the nonsignificantsides of the charts. This is due to the factthat they were not reported or were not includedin multivariable analysis as they had been foundin univariate analyses not to be significant. We arereliant on the reporting of each individual study.Within the constraints outlined above, an attempthas been made at the end of the risk model sectionto summarise and interpret the evidence for riskfactors and adverse outcomes after EVAR.AgeIn total, 24 studies 60,61,63–67,69,71–74,77–79,81,82,84,86–91investigated the role of age in relation to adverseoutcomes after EVAR (Figures 8–12). Age waseither treated as a continuous variable ordichotomised, for example into under 80 years andoctogenarians. 71The evidence showed age to be a risk factor for30-day mortality (Figure 8). For the outcome ofaneurysm-related mortality evidence was mixed(Figure 9). For all-cause mortality all nine studiesin this group correctly identified increasing ageTABLE 31 Patient characteristics of risk modelling studiesStudyNumberGenderof patients Age of population a (% male) Aneurysm diameter bBoult 2007, 60Boult 2006 92 961 75.0 (SD 6.9) years 86% Men 5.8 (SD 1.05) cm; women 5.5 (SD0.9) cmBrewster 2006 61 873 75.7 (SD 7.6) years; range 81.4% 5.68 (SD 1.06) cm49–99 yearsBush 2007 62 2368 72.2 years 99.3% Not reportedButh 2000 63 1892 70 years; range 37–90 years 91% Median 5.6 cm; range 2.8–15 cmButh 2000 64 1554 70 years; range 37–90 years 91.4% Median 5.6 cm; range 2.8–15 cmButh 2002 65 3075 71.7 years 92.7% 5.66 cmButh 2003 66 3595 Not reported Not reported Not reportedCuypers 2000 67 1871 69.7 years 91.8% 5.6 cmDiehm 2007 68 6383 72.4 (SD 7.6) years 93.8% 5.87 cm (calculated)continued49© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessTABLE 31 Patient characteristics of risk modelling studies (continued)StudyNumberGenderof patients Age of population a (% male) Aneurysm diameter bDiehm 2007 91 711 No anaemia 74.6 (SD 7.5)years; anaemia 78.5 (SD 7.5)yearsHobo 2006 69 2846 72.0 (SD 7.5) years 94% 5.8 cmHobo 2007 70 5183 72.6 years; range 43–100 years 93.8% 5.9 cmLange 2005 71 4433 Patients < 80 years: 70.3 (SD6.5) years; octogenarians 83.4(SD 2.9) yearsRange: patients < 80 years:43–79 years; octogenarians:80–100 yearsLeurs 2007 72 1033 DREAM: 70.6 (SD 6.51) years;EUROSTAR: 71.6 (SD 7.67)yearsLeurs 2004 73 676 72.1 years (calculated); range43–96 years90.9% No anaemia 5.7 (SD 0.97) cm; anaemia6.08 (SD 1.22) cmPatients < 80years: 94.8%;octogenarians:90.2%(p < 0.0001)Patients < 80 years: 5.76 (SD 1.04) cm;octogenarians 6.2 (1.22) cm (p < 0.0001)92.7% DREAM: 6.06 (SD 0.89) cm;EUROSTAR: 6.04 (SD 1.02) cm93% 5.67 cmLeurs 2006 74 3499 73.2 years 94.0% 6.1 cmLeurs 2005 75 6017 71.8 years; range 28–100 years 93.5% Max AAA diameter > 6 cm: 28.5%Leurs 2005 76 4233 Not reported; range 37–101 93.7% 5.8 cm; range 4.0–11.0 cmyearsLeurs 2006 77 5892 72.3 years 94.1% 5.86 cmLifeline c 2002 78 1646 73.1 (SD 7.9) years 88.6% 5.57 cm (SD not reported)Lifeline c 2005 79 2664 73.1 (SD 7.8) years; range 88.6% 5.58 (SD 1.02) cm; range 2.1–12.0 cm45–96 yearsLottman 2004 80 3270 Not reported 93% 44% aneurysm diameter < 5.5 cm; 56%aneurysm diameter 5.5 cmMohan 2001 81 2146 Median 70 years; range 37–92years92% 2.1–15.0 (median 5.6) cmPeppelenbosch 4392 Not reported; range 43–1092004 82 years93.2% 57.2 cm (SD not reported); range4.0–14.5 cmRiambau 2001 83 2862 Not reported 92.2% 5.62 cmRuppert 2006 84 5557 72 years; range 41–100 years Not reported 5.85 cm; range 4–14.5 cmSampram 2003 85 703 75 (SD 8.1) years; range48–100 years86% 5.4 (SD 1.0) cm in minor dimension and5.8 (SD 1.1) cm in major dimensionTimaran 2007 86 65,502 Not reported 82.9% Not reportedTorella 2004 87 3992 70–72 years 93% Current devices 5.7 (SD 10.8) cm;withdrawn devices 5.6 (SD 10.5) cmvan Eps 2007 88 5167 72 years; range 43–100 94.3% Patients with normal renal function5.81 (SD 1.08) cm; patients withrenal dysfunction 5.96 (SD 1.17) cm(p < 0.001); Range 4–17.2 cmvan Marrewijk 3595 71.2 (calculated); range 37– 94% 5.7 cm (SD not reported)2004 89 100 yearsZarins 2006 90 923 71.3–74.6 years across groups 88–90%across groups5.7 (SD 1.5) cma Mean age unless stated otherwise.b Mean cm unless stated otherwise.c Lifeline Registry of Endovascular Aneurysm Repair.50

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyTimaran 2007 86Buth 2002 65a Leurs 2006 74b Lange 2005 71IRFvan Eps 2006 88Not IRFButh 2000 64Sample sizeData sourceStudy dates65,502US2001–20043075EUROSTAR1996–20013499EUROSTAR1996–20064433EUROSTAR1996–20045167EUROSTAR1996–20051554EUROSTAR1994–1999a, Age 70 years or more; b, patients < 80 years of age versus octogenarians.FIGURE 8 Age and 30-day mortality. Studies to the left of the vertical line found age to be an independent risk factor (IRF), whereasthose to the right did not.StudyTorella 2004 87aLeurs 2006 77 Lifeline 2005 79IRF Not IRFPeppelenboschb Lange 2005 71 Boult 2007 60 Leurs 2004 732004 82Sample sizeData sourceStudy dates3992EUROSTAR1994–20024392EUROSTAR1996–20025892EUROSTAR1996–4433EUROSTAR1996–2004961AUS1999–2001676EUROSTAR1998–20042664US[5 years]a, Age 70 years or more; b, patients < 80 years of age versus octogenarians.FIGURE 9 Age and aneurysm-related mortality. Studies to the left of the vertical line found age to be an independent risk factor (IRF),whereas those to the right did not.as an independent risk factor (Figure 10). Resultsfor reintervention were almost all analyses ofEUROSTAR data and most, but not all, studiesconcluded that age was not a risk factor (Figure 11).On balance the mainly EUROSTAR-based evidenceindicates that age is an independent risk factor fortype II endoleak or all types of endoleak (Figure12).Varying interpretations of old age and the way thatdata were handled may affect findings and may© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.explain some of the inconsistency in the results inthis section.GenderA total of 11 studies 60,61,63,64,69,79,81,82,86,87,89investigated the role of gender in relation toadverse outcomes after EVAR (Figures 13–17).The results of the very large recent US-based studyand the smaller, older EUROSTAR study providecontradictory results regarding the association51

Assessment of clinical effectivenessStudyBoultBrewster aLange Leurs Leurs Leurs Lifeline Lifeline Zarins2006 61 2005 71 2007 72 2004 73 2006 77 2002 78 2005 79 2006 902007 60 Not IRFIRFNot IRFSample sizeData sourceStudy dates961 873 4433AUS US EUROSTAR1999–2001 1994–2005 1996–20041033EUROSTAR1999–676EUROSTAR1998–20045892EUROSTAR1996–1646USNot reported2664US[5 years]923US1998–1999a, Patients < 80 years of age versus octogenarians.FIGURE 10 Age and all-cause mortality. Studies to the left of the vertical line found age to be an independent risk factor (IRF), whereasthose to the right did not.StudyIRFBoult LeursaTorella ButhaLange aCuypers Peppelenbosch Hobo2007 60 2007 72 2004 87 2000 63 2005 71 2000 67 2004 82 2006 69Sample sizeData sourceStudy dates961AUS1999–20011033EUROSTAR1999–3992EUROSTAR1994–20021554EUROSTAR1994–19994433EUROSTAR1996–20041871EUROSTAR1994–19994392EUROSTAR1996–20022846EUROSTAR1999–2004a, Conversion to open repair.FIGURE 11 Age and reintervention. Studies to the left of the vertical line found age to be an independent risk factor (IRF), whereasthose to the right did not.between female gender and 30-day mortality(Figure 13). However, given the small numberof female patients in most series the very largestudy is likely to be more reliable. Therefore,there may be a link between female gender and30-day mortality. There is no indication of anylink between female gender and aneurysmrelatedor all-cause mortality (Figures 14 and15). The evidence suggests that gender is not anindependent risk factor for reintervention (Figure16). There is contradictory evidence regardingassociation with endoleak (Figure 17).Pre-existing conditionsIn total, 19 studies 60,64,65,68,69,72–76,78,79,81–83,88–91investigated the role of pre-existing conditionsin relation to adverse outcomes after EVAR. Thestudies assessed the role of a range of pre-existingconditions such as pulmonary insufficiency,diabetes, chronic heart failure, obesity, anaemiaand hypertension (Figures 18–22).The available analyses of EUROSTAR data indicatethat cardiac status, high blood pressure andobesity are not independent risk factors for 30-52

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyIRF Not IRFaButhbButhcButhd Lange Ruppert van Marrewijk Mohan Boult2000 63 2000 64 2003 66 2005 71 2006 84 2004 89 2001 81 2007 60Sample sizeData sourceStudy dates1892EUROSTAR1994–20001554EUROSTAR1994–19993595EUROSTARNot reported4433EUROSTAR1996–20045557EUROSTAR1997–20043595EUROSTAR1996–20022146EUROSTAR1994–2000961AUS1999–2001a, 75+ years of age and early endoleak; b, 75+ years of age and early endoleak; c, type II endoleak; d, all endoleaks, type II and III.FIGURE 12 Age and endoleak. Studies to the left of the vertical line found age to be an independent risk factor (IRF), whereas those tothe right did not.StudyIRFTimaran 2007 86Not IRFButh 2000 64Sample sizeData sourceStudy dates65,502US2001–20041554EUROSTAR1994–1999FIGURE 13 Female gender and 30-day mortality. Studies to the left of the vertical line found gender to be an independent risk factor(IRF), whereas those to the right did not.day mortality. The results regarding diabetes andpulmonary impairment as predictors of 30-daymortality are inconsistent (Figure 18).The analyses for aneurysm-related mortalityshowed inconsistent results for pulmonary status.However, the evidence suggested that diabetes isnot a risk factor for aneurysm-related mortality andbased on one US study hypertension was not found© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.to be a risk factor for aneurysm-related mortality.Evidence on other pre-existing conditions waslacking for this outcome (Figure 19).There were inconsistent results regarding cardiacdisease and all-cause mortality after EVAR. Themajority of studies found that pulmonary status/chronic obstructive pulmonary disease (COPD) wasan independent risk factor for all-cause mortality53

Assessment of clinical effectivenessStudyIRFNot IRFPeppelenbosch2004 82Sample sizeData sourceStudy datesBoult 2007 60 2664961AUS1999–2001Lifeline 2005 79 3992US[5 years]a Torella 2004 87 4392EUROSTAR1994–2002EUROSTAR1996–2002a, Male not female.FIGURE 14 Female gender and aneurysm-related mortality. Studies to the left of the vertical line found gender to be an independentrisk factor (IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60Lifeline 2005 79Sample sizeData sourceStudy dates961AUS1999–20012664US[5 years]FIGURE 15 Female gender and all-cause mortality. Studies to the left of the vertical line found gender to be an independent risk factor(IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60Peppelenbosch2004 82Sample sizeData sourceStudy dates873US1994–2005a Brewster 2006 61 2846961AUS1999–2001Hobo 2006 69 3992EUROSTAR1999–2004b Torella 2004 87 4392EUROSTAR1994–2002EUROSTAR1996–2002a, Conversion to open repair; b, male not female.FIGURE 16 Female gender and reintervention. Studies to the left of the vertical line found gender to be an independent risk factor (IRF),whereas those to the right did not.54

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Studya Buth 2000 63IRFNot IRFvan Marrewijk2004 89Sample sizeData sourceStudy dates1892EUROSTAR1994–2000b Boult 2007 60 1554961AUS1999–2001c Buth 2000 64 961EUROSTAR1994–1999d Boult 2007 60 2146AUS1999–2001Mohan 2001 81 3595EUROSTAR1994–2000EUROSTAR1996–2002a, Early endoleak; b, male gender and type II endoleak; c, endoleak at end of procedure; d, male gender, type I endoleak.FIGURE 17 Female gender and endoleak. Studies to the left of the vertical line found gender to be an independent risk factor (IRF),whereas those to the right did not.Studya Leurs 2005 76IRFNot IRFd Buth 2000 64 e Buth 2002 65f Diehm 2007 68Sample sizeData sourceStudy dates6017EUROSTAR1994–2003b van Eps 2006 88 34995167EUROSTAR1996–2005c Leurs 2006 74 1554EUROSTAR1996–2006EUROSTAR1994–19993075EUROSTAR1996–6383EUROSTAR1996–2005a, Diabetes; b, pulmonary impairment; c, statin use; d, cardiac status, blood pressure; e, cardiac status, blood pressure, pulmonary status,diabetes, obesity; f, diabetes, pulmonary status.FIGURE 18 Pre-existing conditions and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.after EVAR in both the EUROSTAR and the USpopulations. The findings for diabetes as a riskfactor for all-cause mortality were inconsistent. Inone EUROSTAR and one US study hypertensionwas not found to be a risk factor for all-causemortality. Evidence was lacking on other riskfactors (Figure 20).The available analyses suggest that diabetes isnot a risk factor for reintervention/conversion toopen repair. One Australian study concluded thatthe higher the number of pre-existing conditionsthe greater the rates of reintervention whereasall EUROSTAR studies found that pre-existing© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.conditions did not tend to predict reintervention(Figure 21).The studies consistently found that pre-existingconditions were not risk factors for endoleak (Figure22).Renal functionA total of 11 studies 60,61,65,73,78,79,82,83,88,89,91investigated renal function/renal impairment asa potential risk factor for adverse outcomes inmultivariable modelling (Figures 23–27). Althoughall outcomes were considered, the outcome of reinterventionwas only investigated in one study.55

Assessment of clinical effectivenessStudya Zarins 2006 90IRFb PeppelenboschNot IRFd Diehm 2007 68 e Leurs 2004 73Sample sizeData sourceStudy dates923US1998–1999b Diehm 2007 68 43926383EUROSTAR1996–20052004 82 2664EUROSTAR1996–2002c Lifeline 2005 79 6383US[5 years]EUROSTAR1996–2005676EUROSTAR1998–2004a, Peripheral vascular disease; b, pulmonary status; c, hypertension, CAD, MI, CHF, COPD, diabetes; d, diabetes; e, pulmonary insufficiency.FIGURE 19 Pre-existing conditions and aneurysm-related mortality. Studies to the left of the vertical line found pre-existing conditionsto be an independent risk factor (IRF), whereas those to the right did not.IRFNot IRFStudya Buth2002 65b Diehm2007 68c Leurs2007 72d Diehm2007 91e Zarins2006 90Leurs2006 76f Lifeline2005 79g Lifeline2002 78h Riambau2001 83i Diehm2007 68i Leurs2005 75i Leurs2005 76j Leurs2006 74k Lifeline2005 79l Riambau2001 83Sample sizeData sourceStudy dates3075EURO-STAR1996–6383EURO-STAR1996–20052368US2001–2004711EURO-STAR1994–2006923US1998–19995892EURO-STAR1996–2664US[5 years]1646USNotreported2862EURO-STAR1994–19986383EURO-STAR1996–20054233EURO-STAR1994–20046017EURO-STAR1994–20035892EURO-STAR1996–2664US[5 years]2862EURO-STAR1994–1998a, Pulmonary disorder; b, pulmonary status; c, pulmonary status, diabetes; d, pulmonary function, baseline, diabetes, baseline haemomglobin level; e, COPD,PAD; f, CAD/ MI, CHF, COPD; g, COPD, CHF; h, diabetes in those fit for open surgery; i, diabetes; j, statin use; k, hypertension, diabetes; l, hypertension,carotid artery disease or cardiac disease, hyperlipidaemia, pulmonary status, diabetes in patients unfit for open surgery .FIGURE 20 Pre-existing conditions and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.56There was consistent evidence from a small numberof studies that renal impairment affects 30-daymortality after EVAR (Figure 23) but inconsistentevidence of its effects on aneurysm-relatedmortality (Figure 24). The balance of evidencesuggests that renal impairment is an independentrisk factor for all-cause mortality (Figure 25).Analyses of EUROSTAR data indicate no linkbetween renal dysfunction and reintervention(Figure 26) or endoleak (Figure 27) after EVAR.Fitness for open procedureSix studies investigated whether patients’ fitnessfor open procedure determined adverse outcomes

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyIRFa Boult 2007 60Not IRFd Diehm 2007 68 e Leurs 200575 Peppelenbosch f Hobo 2006 692004 82Sample sizeData sourceStudy dates961AUS1999–2001b Leurs 2005 76 58926017EUROSTAR1994–2003EUROSTAR1996–c Leurs 2006 74 28466383EUROSTAR1996–20054233EUROSTAR1994–20044392EUROSTAR1996–2002EUROSTAR1999–2004a, Higher number of pre-existing conditions; b, diabetes; c, statin use; d, pulmonary status, diabetes; e, diabetes leading to reintervention;f, systemic comorbidities.FIGURE 21 Pre-existing conditions and reintervention. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.Studya Buth2003 66IRFa vanMarrewijk2004 89 961Not IRFBoult2007 60 2146b Mohanc Diehm2001 81 2007 68d Leurs2005 76e Buth2000 64b vanMarrewijk2004 89e Leurs2005 75Sample sizeData sourceStudy dates3595EUROSTARNot reported3595EUROSTAR1996–2002AUS1999–2001EUROSTAR1994–20006383EUROSTAR1996–20056017EUROSTAR1994–20031892EUROSTAR1994–20003595EUROSTAR1996–20024233EUROSTAR1994–2004a, Blood pressure index < 0.87; b, obesity; c, pulmonary status, diabetes; d, hypertension, diabetes; e, cardiac status, blood pressure indexfor endoleak at completion of procedure; f, hypertension.FIGURE 22 Pre-existing conditions and endoleak. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.after EVAR (Figures 28–32). Five of these were basedon EUROSTAR data 64,65,73,82,87 whereas one wasbased on a national Australian audit. 60There was inconsistent evidence linking fitnessand 30-day mortality but the more recent analysiswith a larger cohort suggested there might bean association (Figure 28). On balance, analysesindicate that fitness for open procedure is linked to© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.aneurysm-related mortality (Figure 29). Evidencewas lacking to link fitness for open procedure andall-cause mortality (Figure 30), and, on balance,fitness was not an independent risk factor forreintervention (Figure 31) or endoleak (Figure 32).ASA statusIn total, 12 studies 60,62–65,69,77,81,82,88–90 investigated therole of patients’ ASA status in relation to adverse57

Assessment of clinical effectivenessStudyBrewster 2006 61 IRF Not IRFButh 2002 65 van Eps 2006 88Sample sizeData sourceStudy dates873US1994–20053075EUROSTAR1996–5167EUROSTAR1996–2005FIGURE 23 Renal function and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyIRFPeppelenboschNot IRFBoult 2007 60 Leurs 2004 73 Lifeline 2005 79Sample sizeData sourceStudy datesBrewster 2006 61 4392873US1994–2005EUROSTAR1996–2002961AUS1999–20012004 82 Not IRF676EUROSTAR1998–20042664US[5 years]FIGURE 24 Renal function and aneurysm-related mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyBoult 2007 60 Lifeline 2002 78 Lifeline 2005 79IRFRiambau 2001 83Sample sizeData sourceStudy dates961AUS1999–2001873US1994–2005Brewster 2006 61 28621646USNot reported2664US[5 years]EUROSTAR1994–199858FIGURE 25 Renal function and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyIRFNot IRFPeppelenbosch2004 82Sample sizeData sourceStudy dates4392EUROSTAR1996–2002FIGURE 26 Renal function and reintervention. Studies to the left of the vertical line found pre-existing conditions to be an independentrisk factor (IRF), whereas those to the right did not.StudyIRFNot IRFvan Eps 2006 88van Marrewijk2004 89Sample sizeData sourceStudy dates5167EUROSTAR1996–20053595EUROSTAR1996–2002FIGURE 27 Renal function and endoleak. Studies to the left of the vertical line found pre-existing conditions to be an independent riskfactor (IRF), whereas those to the right did not.StudyButh 2002 65 IRFNot IRFButh 2000 64Sample sizeData sourceStudy dates3075EUROSTAR1996–20011554EUROSTAR1994–1999FIGURE 28 Fitness for open procedure and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to bean independent risk factor (IRF), whereas those to the right did not.59© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessStudyTorella 2004 87 Peppelenbosch Leurs 2004 73IRF Not IRF2004 82Sample sizeData sourceStudy dates3992EUROSTAR1994–20024392EUROSTAR1996–2002676EUROSTAR1998–2004FIGURE 29 Fitness for open procedure and aneurysm-related mortality. Studies to the left of the vertical line found pre-existingconditions to be an independent risk factor (IRF), whereas those to the right did not.IRF Not IRFStudy Leurs 2004 73Sample sizeData sourceStudy dates676EUROSTAR1998–2004FIGURE 30 Fitness for open procedure and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to bean independent risk factor (IRF), whereas those to the right did not.IRFNot IRFStudyBoult 2007 60aTorella 2004 87Peppelenbosch2004 82Sample sizeData sourceStudy dates961AUS1999–20013992EUROSTAR1994–20024392EUROSTAR1996–2002a, Late conversion to OR.FIGURE 31 Fitness for open procedure and reintervention. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.60

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48IRFNot IRFMohan 2001 81StudyButh 2000 64Boult 2007 60Sample sizeData sourceStudy dates2146EUROSTAR1994–20001554EUROSTAR1994–1999961AUS1999–2001FIGURE 32 Fitness for open procedure and endoleak. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.outcomes after EVAR (Figures 33–37). The majorityof the studies were based on EUROSTAR data.According to EUROSTAR data, ASA classes IIIand IV are predictive of statistically significantlyworse 30-day mortality (Figure 33). Evidencefor aneurysm-related mortality was inconsistent(Figure 34). With the exception of a largeUS study, all analyses found ASA to be anindependent risk factor for all-cause mortality(Figure 35). On balance, ASA status was not foundto be a significant independent risk factor forreintervention (Figure 36) or endoleak (Figure 37).Smoking statusSeven studies 60,64,66,76,80,81,89 investigated smokingstatus as a risk factor for adverse outcomes afterEVAR.The evidence suggests that smoking status isnot associated with adverse outcomes afterEVAR (Figures 38–42). However, the evidenceinvestigating smoking and mortality after EVAR isvery limited.Aneurysm sizeIn total, 19 studies 60,61,63,64,67,69,72,73,76,78,79,81,82,84,85,87–90investigated aneurysm size as a potential risk factorfor adverse outcomes in multivariable modelling(Figures 43–47).More recent and larger cohort analysisdemonstrates that aneurysm size is an independentrisk factor for 30-day mortality (Figure 43).Evidence also suggests that it is an independentrisk factor for aneurysm-related mortality (Figure44) and all-cause mortality (Figure 45). Evidencefor aneurysm size as an independent risk factor forreintervention (Figure 46) and endoleaks (Figure 47)is inconsistent.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.Aortic neck and aneurysm angleEight studies 60,64,70,74,76,81,82,87 investigated aorticneck and aneurysm angle as potential risk factorsfor adverse outcomes in multivariable modelling(Figures 48–52). With the exception of oneAustralian study 60 all were based on EUROSTARpopulations.The balance of evidence suggests no effect of aorticneck and aneurysm angle on 30-day mortality(Figure 48), aneurysm-related mortality (Figure 49)or all-cause mortality (Figure 50). Evidence withregard to reintervention (Figure 51) and endoleak(Figure 52) was mixed allowing no firm conclusionsto be drawn.Aortic neck lengthNine studies 60,66,67,74,76,81,82,87,89 investigated aorticneck length as a potential risk factor for adverseoutcomes in multivariable modelling (Figures 53–57). With the exception of one Australian study 60 allwere based on EUROSTAR populations.There was limited evidence available for 30-daymortality (Figure 53). Evidence with regard toaneurysm-related mortality was inconsistent butnone of the EUROSTAR analyses found it to bean independent risk factor (Figure 54). Evidencefor all-cause mortality was limited but suggestiveof no effect (Figure 55). Evidence regardingreintervention rates was mixed (Figure 56) as wasthe evidence for endoleak (Figure 57) with possibledifferences with type of endoleak.Graft configuration and device typeIn total, 10 studies 60,61,64,67,69,81,82,84,87,89 investigatedthe roles of graft configuration and device type inadverse outcomes after EVAR (Figures 58–62).61

Assessment of clinical effectivenessStudyButh 2000 64Buth 2002 65IRFvan Eps 2006 88Not IRFBush 2007 62Sample sizeData sourceStudy dates1892EUROSTAR1994–2000a Buth 2000 63 22,3681554EUROSTAR1994–19993075EUROSTAR1996–5167EUROSTAR1996–2005US2001–2004a, ASA III and IV.FIGURE 33 ASA class and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to be an independentrisk factor (IRF), whereas those to the right did not.StudyBoult 2007 60IRFa Leurs 2006 74Not IRFPeppelenbosch2004 82Sample sizeData sourceStudy dates961AUS1999–20015892EUROSTAR1996–4392EUROSTAR1996–2002a, ≥ ASA III.FIGURE 34 ASA class and aneurysm-related mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.The evidence regarding graft configuration/device type and 30-day mortality (Figure 58) andall-cause mortality (Figure 60) was too limited todraw conclusions. The balance of evidence suggeststhat there might be a link between device type andaneurysm-related mortality (Figure 59). Evidenceregarding graft configuration/device type andreintervention (Figure 61) and endoleak (Figure 62)was inconsistent.Summary statementsA large number of studies have modelled the riskof mortality and other adverse outcomes afterEVAR. We do not have definitive evidence on all of62

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyBoult 2007 60Zarins 2006 90IRFa Leurs 2006 74Not IRFBush 2007 62Sample sizeData sourceStudy dates3075EUROSTAR1996–961AUS1999–2001923US1998–1999Buth 2002 65 22,3685892EUROSTAR1996–US2001–2004a, ASA ≥ III.FIGURE 35 ASA class and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to be an independentrisk factor (IRF), whereas those to the right did not.StudyIRFBoult 2007 60Not IRFHobo 2006 69Peppelenbosch2004 82Sample sizeData sourceStudy dates961AUS1999–20012846EUROSTAR1999–20044392EUROSTAR1996–2002FIGURE 36 ASA class and reintervention. Studies to the left of the vertical line found pre-existing conditions to be an independent riskfactor (IRF), whereas those to the right did not.the risk factors and outcomes explored. The firmestevidence supports the following conclusions.30-day mortalityIncreasing age is a risk factor for 30-day mortalityand the results of a very large recent US-basedstudy suggest that there may be a link betweenfemale gender and this outcome. Cardiacstatus, high blood pressure and obesity were notfound to be independent risk factors for 30-daymortality but there was consistent evidence froma small number of studies that renal impairment© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.affects this outcome. There was a suggestion ofa link between fitness and 30-day mortality and,according to EUROSTAR data, ASA classes III andIV are predictive of statistically significantly worse30-day mortality. Aneurysm size is likely to be anindependent risk factor for 30-day mortality butthe balance of evidence suggests no independenteffect of aortic neck and aneurysm angle. Theevidence regarding graft configuration/devicetype and 30-day mortality was too limited to drawconclusions.63

Assessment of clinical effectivenessStudyIRFa Boult 2007 60Not IRFb Boult 2007 60Mohan 2001 81b van Marrewijk2004 89Buth 2000 64Sample sizeData sourceStudy dates961AUS1999–2001961AUS1999–20012146EUROSTAR1994–20003595EUROSTAR1996–20021554EUROSTAR1994–1999a, Type II; b, type I.FIGURE 37 ASA class and endoleak. Studies to the left of the vertical line found pre-existing conditions to be an independent risk factor(IRF), whereas those to the right did not.StudyIRFNot IRFButh 2000 64Sample sizeData sourceStudy dates1554EUROSTAR1994–1999FIGURE 38 Smoking status and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60Sample sizeData sourceStudy dates961AUS1999–2001FIGURE 39 Smoking status and aneurysm-related mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.64Aneurysm-related mortalityThere is no indication of a link between femalegender and aneurysm-related mortality. Theevidence suggested that diabetes and (based onone US study) hypertension were not risk factorsfor this outcome. Evidence on other pre-existingconditions was lacking. On balance, analysesindicate that fitness for open procedure is linkedto aneurysm-related mortality. Aneurysm size isalso likely to be an independent risk factor for thisoutcome. The balance of evidence suggests noeffect of aortic neck and aneurysm angle on thisoutcome but a possible link between device typeand aneurysm-related mortality.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyIRFNot IRFBoult 2007 60Lottmann 2004 80Sample sizeData sourceStudy dates961AUS1999–20013270EUROSTAR1994–2001FIGURE 40 Smoking status and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60Lottmann 2004 80Sample sizeData sourceStudy dates961AUS1999–20013270EUROSTAR1994–2001FIGURE 41 Smoking status and reintervention. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyIRF Not IRFvan Boult 2007 60Marrewijk2004 89a Buth 2003 66b Mohan2001 81 Leurs 2005 75c Buth 2000 64d Lottmann2004 80Sample sizeData sourceStudy dates3595EUROSTAR1996–2002961AUS1999–20013595EUROSTARNot reported2146EUROSTAR1994–20004233EUROSTAR1994–20041554EUROSTAR1994–19993270EUROSTAR1994–2001a, Current smoking decreased risk of type II endoleak; b, those who had stopped > longer ago increased risk of endoleak; c, negativeassociation between current smoking and endoleak; d, risk reduction in smokers for late endoleak (type II).FIGURE 42 Smoking status and endoleak. Studies to the left of the vertical line found pre-existing conditions to be an independent riskfactor (IRF), whereas those to the right did not.65© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessStudyIRFvan Eps 2006 88Not IRFButh 2000 64Sample sizeData sourceStudy dates5167EUROSTAR1996–20051554EUROSTAR1994–1999FIGURE 43 Aneurysm size and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyPeppelenboschTorella 2004 87Zarins 2006 90 Lifeline 2005 79IRFBrewster2006 61Not IRFLeurs 2004 73Sample sizeData sourceStudy dates4392EUROSTAR1996–20023992EUROSTAR1994–2002961AUS1999–2001923US1998–19992664US[5 years]873US1994–2005676EUROSTAR1998–2004Study2004 82 Boult 2007 60 Not IRFFIGURE 44 Aneurysm size and aneurysm-related mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.Brewster Leurs Buth 2002 652006 61 2004 73Lifeline Boult2002 78 2007 60Leurs 2007 72ZarinsIRFLifeline2005 792006 90 2664Sample sizeData sourceStudy dates873US1994–2005676EUROSTAR1998–20043075EUROSTAR1996–1646USNot reported961AUS1999–20011033EUROSTAR1999–923US1998–1999US[5 years]66FIGURE 45 Aneurysm size and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48IRFNot IRFStudyBoult 2007 60Zarins 2006 90Sampram2003 85a Torella 2004 87Pepplenbosch2004 82b Cuypers2000 67Hobo 2006 69Sample sizeData sourceStudy dates961AUS1999–2001923US1998–1999703US1996–20023992EUROSTAR1994–20024392EUROSTAR1996–20021871EUROSTAR1994–19992846EUROSTAR1999–2004a, Late conversion to open repair; b, conversion to open repair only.FIGURE 46 Aneurysm size and reintervention. Studies to the left of the vertical line found pre-existing conditions to be an independentrisk factor (IRF), whereas those to the right did not.IRFNot IRFStudya Boult 2007 60 Ruppert Mohan 2001 812006 84Leurs 2005 75 b Boult 2007 60c Mohan2001 81van Marrewijk2004 89Buth 2000 64Sample sizeData sourceStudy dates961AUS1999–20015557EUROSTAR1997–20042146EUROSTAR1994–20004233EUROSTAR1994–2004961AUS1999–20012146EUROSTAR1994–20003595EUROSTAR1996–20021892EUROSTAR1994–2000a, Type I endoleak; b, type II endoleak; c, proximal endoleak.FIGURE 47 Aneurysm size and endoleak. Studies to the left of the vertical line found pre-existing conditions to be an independent riskfactor (IRF), whereas those to the right did not.All-cause mortalityIncreasing age had a self-evident role in all-causemortality, but there is no indication of any linkbetween female gender and this outcome. Themajority of studies found that pulmonary status/COPD was an independent risk factor for all-causemortality after EVAR but evidence was lacking orinconsistent on other comorbidities. The balanceof evidence did suggest that renal impairment isan independent risk factor for all-cause mortality.With the exception of a large US study, all analysesfound ASA status to be an independent risk factorfor all-cause mortality. The very limited evidence© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.suggests that smoking status is not associated withadverse outcomes after EVAR. Aneurysm size islikely to be an independent risk factor for all-causemortality but the balance of evidence suggestsno effect of aortic neck and aneurysm angle. Theevidence regarding graft configuration/device typeand all-cause mortality was too limited to drawconclusions.ReinterventionThe evidence suggests that age and gender werenot risk factors for reintervention. The availableanalyses also suggest that diabetes is not a risk67

Assessment of clinical effectivenessIRFNot IRFStudyButh 2000 64Hobo 2007 70Sample sizeData sourceStudy dates1554EUROSTAR1994–19995183EUROSTAR1996–2005FIGURE 48 Aortic neck/aneurysm angle and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to bean independent risk factor (IRF), whereas those to the right did not.IRFNot IRFStudyBoult 2007 60Hobo 2007 70Peppelenbosch2004 82Torella 2004 87Sample sizeData sourceStudy dates961AUS1999–20015183EUROSTAR1996–20054392EUROSTAR1996–20023992EUROSTAR1994–2002FIGURE 49 Aortic neck/aneurysm angle and aneurysm-related mortality. Studies to the left of the vertical line found pre-existingconditions to be an independent risk factor (IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60 Hobo 2007 70 Leurs 2006 74Sample sizeData sourceStudy dates961AUS1999–20015183EUROSTAR1996–20053499EUROSTAR1996–200668FIGURE 50 Aortic neck/aneurysm angle and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions tobe an independent risk factor (IRF), whereas those to the right did not.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48StudyIRF Not IRFa Hobo 2007 70 Boult 2007 60 b Torella 2004 87 c Hobo 2007 70 Peppelenbosch Leurs 2006 742004 82Sample sizeData sourceStudy dates5183EUROSTAR1996–2005961AUS1999–20013992EUROSTAR1994–20025183EUROSTAR1996–20054392EUROSTAR1996–20023499EUROSTAR1996–2006a, Long term; b, late conversion to open repair; c, 30 days.FIGURE 51 Aortic neck/aneurysm angle and reintervention. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyIRF Not IRFa Boult 2007 60 b Hobo 2007 70 Leurs 2005 75 c Boult 2007 60 d Buth 2000 64Mohan 2001 81Sample sizeData sourceStudy dates961AUS1999–20015183EUROSTAR1996–20054233EUROSTAR1994–2004961AUS1999–20011554EUROSTAR1994–19992146EUROSTAR1994–2000a, Type I; b, proximal type I ; c, type II ; d, end of procedure.FIGURE 52 Aortic neck/aneurysm angle and endoleak. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.factor for reintervention/conversion to open repair.One Australian study concluded that the higherthe number of pre-existing conditions the greaterthe rate of reintervention whereas all EUROSTARstudies found that pre-existing conditions did nottend to predict reintervention. Single analysesof EUROSTAR data indicate no link betweenrenal dysfunction and reintervention after EVAR.On balance, fitness and ASA status were notindependent risk factors for this outcome.EndoleakOn balance, the evidence indicates that age isan independent risk factor for type II endoleakor all types of endoleak. However, the studiesconsistently found that pre-existing conditionswere not risk factors for endoleak. Single analysesof EUROSTAR data indicate no link between renaldysfunction and endoleak. On balance, fitness andASA status were not independent risk factors forthis outcome.69© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectivenessStudyIRFNot IRFa Leurs 2006 74Leurs 2006 77 3499Sample sizeData sourceStudy datesa, 1.5 cm3499EUROSTAR1996–2006EUROSTAR1996–2006FIGURE 53 Aortic neck length and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.StudyaLeurs 2006 74IRF Not IRFBoult 2007 60 Peppelenbosch Torella 2004 872004 82Sample sizeData sourceStudy dates961AUS1999–20014392EUROSTAR1996–20023992EUROSTAR1994–20023499EUROSTAR1996–2006a, 1.1 – 1.5 cm vs > 1.5 cmFIGURE 54 Aortic neck length and aneurysm-related mortality. Studies to the left of the vertical line found pre-existing conditions to bean independent risk factor (IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60Leurs 2006 74Sample sizeData sourceStudy dates961AUS1999–20013499EUROSTAR1996–200670FIGURE 55 Aortic neck length and all-cause mortality. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Studya Cuypers 2000 67IRFNot IRFPeppelenbosch2004 82 Leurs 2006 74Sample sizeData sourceStudy dates1871EUROSTAR1994–1999b Torella 2004 87 9613992EUROSTAR1994–2002Boult 2007 60 4392AUS1999–2001EUROSTAR1996–20023499EUROSTAR1996–2006a, Conversion to open repair; b, late conversion to open repair.FIGURE 56 Aortic neck length and reintervention. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.Studya Mohan2001 81b Buth2003 66vanMarrewijkIRFc Boultd Leurs2007 62 2006 74Not IRFb Boult2007 60e Leurs2005 75f Leurs2006 74Sample sizeData sourceStudy dates2146EUROSTAR1994–20003595EUROSTARNot reported2004 89 9613595EUROSTAR1996–2002AUS1999–20013499EUROSTAR1996–2006961AUS1999–20014233EUROSTAR1994–20043499EUROSTAR1996–2006a, Proximal endoleak; b, type II endoleak; c, type I endoleak; d, proximal type I endoleak except for 1.1–1.5 cm vs > 1.5 cm; e, negativecorrelation; f, distal type I endoleak except for 1.5 cm and type III endoleak.FIGURE 57 Aortic neck length and endoleak. Studies to the left of the vertical line found pre-existing conditions to be an independentrisk factor (IRF), whereas those to the right did not.Discussion of assessmentof clinical effectivenessCurrently, the EVAR trial 1, 42,43 EVAR trial 2 46 andDREAM 40,41 studies represent the best randomisedevidence for evaluating EVAR. EVAR trial 1 andDREAM provide evidence that EVAR reducesoperative mortality compared with open repair inpatients considered to be fit for both procedures.EVAR is associated with a reduction in aneurysmrelatedmortality over the medium term (up to4 years after randomisation in EVAR trial 1 and2 years in DREAM) but there is no significant© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.difference in all-cause mortality between EVARand open repair at mid-term follow-up. The reasonfor the failure of the short-term benefit of EVARover open repair to translate into an advantage inthe longer term is unclear. One important factoris that patients requiring surgery for AAA are ata high risk of mortality. Because EVAR is a lesstraumatic surgical procedure than open repair,fewer people die as an immediate result of theprocedure. However, these high-risk patientsdie within a relatively short time scale and soby 4 years postoperatively the mortality rate inpatients treated with EVAR or with open repair is71

Assessment of clinical effectivenessStudyIRFNot IRFButh 2000 64Sample sizeData sourceStudy dates1554EUROSTAR1994–1999FIGURE 58 Graft configuration/device type and 30-day mortality. Studies to the left of the vertical line found pre-existing conditions tobe an independent risk factor (IRF), whereas those to the right did not.Studya Torella 2004 87 b Peppelenbosch Boult 2007 60IRF Not IRF2004 82Sample sizeData sourceStudy dates3992EUROSTAR1994–20024392EUROSTAR1996–2002961AUS1999–2001a, Old devices; b, association with Stentor and Vanguard devices.FIGURE 59 Graft configuration/device type and aneurysm-related mortality. Studies to the left of the vertical line found pre-existingconditions to be an independent risk factor (IRF), whereas those to the right did not.StudyIRFNot IRFBoult 2007 60Sample sizeData sourceStudy dates961AUS1999–2001FIGURE 60 Graft configuration/device type and all-cause mortality. Studies to the left of the vertical line found pre-existing conditionsto be an independent risk factor (IRF), whereas those to the right did not.72the same. Other reasons why the mortality rate inthe EVAR-treated patients converges with that ofthe open repair patients include the higher rateof complications and the need for reinterventionsin the former group, which are not offset byany increase in HRQoL, possibly because of theincreased level of monitoring required with EVARbecause of the risk of complications.Analysis of the EVAR trial data 23 did not findany evidence that a benefit of EVAR over openrepair could be predicted using the CPI score for

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48IRFNot IRFStudyCuypers 2000 67Brewster 2006 61Boult 2007 60Hobo 2006 69Peppelenbosch2004 82Sample sizeData sourceStudy dates1871EUROSTAR1994–1999873US1994–2005961AUS1999–20012846EUROSTAR1999–20044392EUROSTAR1996–2002a, Reintervention or late conversion to open repair.FIGURE 61 Graft configuration/device type and reintervention. Studies to the left of the vertical line found pre-existing conditions to bean independent risk factor (IRF), whereas those to the right did not.IRFNot IRFStudya Ruppert 2006 84b Hobo 2007 70Boult 2007 60c Ruppert 2006 84Mohan 2001 81van Marrewijk2004 89Buth 2000 64Sample sizeData sourceStudy dates5557EUROSTAR1997–20045183EUROSTAR1996–2005961AUS1999–20015557EUROSTAR1997–20042146EUROSTAR1994–20003595EUROSTAR1996–20021554EUROSTAR1994–1999a, AneuRx, Talent and Fortron devices; b, excluder and Talent for 30-day proximal type I endoleak. Talent and Zenith for long-termproximal type I endoleaks; c, device type (tube, tapered or bifurcated).FIGURE 62 Graft configuration/device type and endoleak. Studies to the left of the vertical line found pre-existing conditions to be anindependent risk factor (IRF), whereas those to the right did not.preoperative fitness. A large number of studieshave modelled the risk of mortality and otheradverse outcomes following EVAR. These do notprovide definitive evidence but age, gender, renalimpairment, fitness, ASA class and aneurysm sizemay be predictive of poorer 30-day survival. Theremay be a link between fitness for open procedure,aneurysm size and device type and aneurysmrelatedmortality. In terms of all-cause mortality,pulmonary status, renal impairment, ASA class andaneurysm size might adversely affect this outcome.We did not consistently find any risk factors thatwere predictive of reintervention. For the outcomeof endoleak only age was found to be a possibleindependent risk factor.Although measures validated for open repair havebeen applied to EVAR, and age, aneurysm size,ASA class and the clinician’s definition of ‘fitness’do appear to be associated with outcomes, thereis currently no fully validated risk scoring toolto assist clinical decision-making. One study 21has produced an internally validated model forpredicting a wide range of short- and long-term73© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of clinical effectiveness74outcomes following EVAR. The model uses eightvariables (aneurysm size, age, ASA score, gender,serum creatinine, aortic neck angle, infrarenal neckdiameter and infrarenal neck length) to predictrisk of perioperative mortality and morbidity,mid-term survival (3 and 5 years) and need forreintervention. Further research into subgroups ofpatients who may benefit particularly from EVAR iswarranted.There is limited RCT evidence comparing EVARwith non-surgical management in patients unfit foropen repair. EVAR trial 2 46 found no differences inmortality outcomes between groups but this findingcannot be taken as definitive because substantialnumbers of patients randomised to non-surgicalmanagement crossed over to receive surgical repairof their aneurysm, which would be expected todilute the difference between the arms. In effect,this trial was a comparison of EVAR with delayedaneurysm repair, except that the rules governingwhen to intervene were not defined. A trialdesigned and conducted specifically to address thisquestion would be helpful.The results from these trials are complemented bydata from registries, in particular the EUROSTARregistry data relating to devices in current use. 54The 30-day mortality rate of 2.3% in this registryis comparable with the rate of 1.7% in the EVARarm of the EVAR trial 1 RCT. In the UK NVD 16the crude operative mortality rate followingopen repair of unruptured aneurysm was 6.8%,compared with 4.7% in the open repair arm ofEVAR trial 1. Overall cumulative survival followingEVAR was 61% with follow-up of up to 8 years.The EUROSTAR registry provides a largesample for assessing complications after EVARwith follow-up of up to 7 years compared withthe relatively small sample available from thetrials. The cumulative rate of rupture from theEUROSTAR data was 3.1%, that of endoleak 32.5%and reintervention 18%. Few data on rupture wereavailable from the trials. The rate of endoleak fromthe trials was lower (about 20%) but the cumulativerate of reintervention in EUROSTAR was similarto the 4-year point estimate for the EVAR groupin EVAR trial 1 (20%) 43 but lower than that fromEVAR trial 2 (26% 46 ), probably reflecting the lowerfitness of the patient population in this trial.Several relevant trials are in progress includingACE (EVAR versus open repair), 49 OVER (largeRCT similar to EVAR trial 1 in a US population) 50and CAESAR (EVAR versus surveillance for smallaneurysms). 52 A small RCT in Nottingham 47indicated that it is feasible to randomise patientswith ruptured AAAs to immediate EVAR or openrepair and a further trial addressing this patientgroup (Amsterdam Acute Aneurysm Trial 48 ) is inprogress. The overall body of randomised evidencerelevant to EVAR is thus expected to increase in thenext few years.Other relevant evidenceAlthough the clinical review focused on identifyingthe most rigorous and useful evidence, some studydesigns were precluded from consideration by theprespecified exclusion criteria. A recent study bySchermerhorn et al. 96 compared outcomes followingEVAR and open repair in large matched cohorts ofMedicare recipients in the USA. It is discussed herebecause of its relevance to the economic model (seeChapter 4, York economic assessment).This study used administrative data to identifyMedicare beneficiaries who had undergone electiveAAA repair during 2001–4. To control for nonrandomassignment of patients to proceduresthey created matched cohorts of patients afterconstructing logistic regression models thatpredicted the likelihood of undergoing EVAR(propensity score). Each patient who underwentEVAR was matched with the patient with theclosest propensity score who underwent openrepair. The 61,598 patients aged 67 years or olderwho underwent AAA repair were reduced to twomatched cohorts with 22,830 patients in each(45,660 patients altogether). The average age ofthe patients was 76 years and approximately 80%were male. Perioperative (within 30 days) and longterm(during available follow-up) outcomes wereevaluated.The mortality rate within 30 days was 1.2% afterEVAR and 4.8% after open repair (relative risk foropen repair 4.00, 95% CI 3.51 to 4.56, p < 0.001),an absolute difference of 3.6%. The absoluteadvantage of EVAR over open repair increased withincreasing age: from 2.1% absolute risk reductionat 67–69 years to 8.5% at 85 years or older. Allmajor perioperative medical complications wereless likely after EVAR than after open repair.Conversion from EVAR to open repair was requiredin 1.6% of patients. Some vascular and abdominalsurgical complications were more common afteropen repair than after EVAR, as were complicationsrelated to laparotomy. The mean length of hospitalstay was 3.4 days after EVAR and 9.3 days afteropen repair (p < 0.001).

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48The early survival benefit from EVAR persisted forabout 3 years in the whole population, after whichtime the survival curves were similar. The benefitlasted less than 18 months in patients aged 67–74years but for at least 4 years in those aged 85 yearsand older. Rupture rates were higher in the EVARgroup (1.8% versus 0.5% at 4 years, p < 0.001),as were AAA-related reinterventions (9.0%versus 1.7% at 4 years, p < 0.001). Laparotomyrelatedcomplications were more frequent in theopen repair group (9.7% versus 4.1% at 4 years,p < 0.001).Important features of this study were that it used alarge sample drawn from routine clinical practice,although reflecting practice in the USA rather thanin the UK. Patients were followed to the 4-yeartime point, comparable with published data fromthe EVAR trial 1 RCT. The finding of an earlymortality benefit from EVAR but no differencebetween groups in the longer term is similar tothe findings of the EVAR trial 1 and DREAMstudies. The study provides important data on therelationship between age and the benefit of EVARrelative to open repair. It also identified a higherrate of laparotomy-related complications in theopen repair group; such complications were nottaken into account in previous analyses. 96 This maysuggest that the increased risk of non-AAA-relatedreinterventions following open repair may offsetthe increased risk of AAA-related reinterventionsfollowing EVAR.Limitations of the study reflect its non-randomiseddesign and its reliance on administrative data. Theuse of propensity scoring produced two cohortsclosely matched on known prognostic factors butcould not rule out differences between groups inunknown or unmeasured factors that might havean influence on prognosis.Data on aneurysm size were not available in theadministrative database and so it is difficult to saywhether the populations included patients notmeeting UK guidelines for AAA repair. Similarly,anatomic suitability for EVAR could not bedetermined from the available data and so it isunclear how many patients were assigned to openrepair because they were not suitable for EVAR. 96Although, as noted above, the study reports onsurgical complications and laparotomy-relatedcomplications and reinterventions, it does notreport on EVAR-specific complications such asendoleak.In conclusion, this large observational study 96provides data on perioperative and follow-upoutcomes from large cohorts of patients treatedwith EVAR and open repair in routine clinicalpractice. These data supplement and generallysupport the findings of RCTs in patients withunruptured AAAs who are fit for both procedures(EVAR trial 1 and DREAM). However, thelimitations of observational study design andreliance on administrative data should be borne inmind.75© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 4Assessment of cost-effectiveness evidenceSystematic review of existingcost-effectiveness evidenceMethodsA broad range of studies was considered forinclusion in the assessment of cost-effectiveness,including economic evaluations conductedalongside trials and modelling studies. Onlyfull economic evaluations that compared twoor more options and considered both costs andconsequences were included.The following databases were searched forrelevant published literature: EconLIT, EMBASE,Health Economic Evaluations Databases (HEED),MEDLINE, IDEAS and NHS Economic EvaluationDatabase (NHS EED). Full details of the mainsearch strategy for this review are presented inAppendix 1.One reviewer assessed all obtained titles andabstracts for inclusion. The quality of the costeffectivenessstudies was assessed accordingto a checklist updated from that developed byDrummond and Jefferson. 97 This information issummarised within the text of the report, alongsidea detailed critique of the study and the relevance tothe UK NHS. The complete version of the checklistfor each study considered is presented in Appendix2.ResultsThe systematic literature search identified sevenstudies that met the inclusion criteria for the costeffectivenessreview. The cost-effectiveness reviewalso considered the Medtronic submission to NICE.The following sections provide a detailed critiqueof the cost-effectiveness evidence from the includedstudies and an assessment of the quality andrelevance of the data from the perspective of theUK NHS. A quality assessment checklist is providedfor each study.Cost-effectiveness studiesfocusing on the EVAR trial1 population/levelThis section considers economic evaluation studiesfocusing on a patient population similar to that inEVAR trial 1 (i.e. patients requiring surgery andconsidered fit for open repair).Patel et al. The cost-effectivenessof endovascular repair versus opensurgical repair of abdominal aorticaneurysms: a decision analysis model 105OverviewThis study was designed to determine whetherEVAR is a cost-effective alternative to open surgeryin the treatment of AAAs. The base case wasdefined as 70-year-old men with an AAA of 5 cmin diameter. This study was conducted before thepublication of trial results for either EVAR trial 1 orDREAM.The authors developed a Markov decision modelto compute lifetime QALYs and costs for ahypothetical cohort of patients who underwenteither EVAR or open surgery. In the model, oncea patient has undergone a procedure, either EVARor open surgery, the outcomes include a successfulrepair or any of a number of complications.Effectiveness, resource use and cost data werederived from the literature. Figure 63 provides aschematic for the Markov model developed by theauthors of this study.Summary of effectiveness dataEffectiveness data were derived from the literaturewith preference given to data derived from largemulticentre studies. For open surgery a largeCanadian study was used to derive mortality andmorbidity rates. For EVAR, because there were noRCTs at the time that this study was published,mortality rates were taken as an average of those inthe three largest trials and the occurrence of longtermmorbidity was estimated from other sources.It should be noted that their review found EVAR77© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidence70-year-old cohort with 5 cmabdominal aortic aneurysmOpen surgical repairDeathEndovascular repairSuccessful repairReoperationStrokeDialysis-dependent renal failureAmputationMyocardial infarctionGraft thrombosisEndoleakSuccessful repairLONG-TERMDEATHFIGURE 63 Schematic of model from Patel et al., 105 with permission from Elsevier.to have lower stroke, myocardial infarction, majoramputation and dialysis-dependent renal failurerates than open repair during primary admission.For reinterventions, probabilities for both initialprocedures were derived from the literature. Thestudy also considered the immediate and lateconversions of EVAR to open surgery.A quality adjustment factor was assigned for eachyear of survival of a patient who had a majormorbidity, for example a quality adjustmentfactor of 0.4 was used for a patient who had hada major stroke. Quality adjustment for temporaryconditions was achieved through subtractingdisutilities from the overall QALY estimate.Although it is not made clear in the study, itwould appear that patients who are experiencingno complications are assigned a utility of 1. Thiswould appear inappropriate given the age andgeneral ill health of the patients being considered.QALYs were discounted at a rate of 3% per annum.Table 32 presents some of the key effectivenessparameters used in the model.Summary of resourceutilisation and cost dataThe costs were derived from the cost accountingsystem at New York Presbyterian Hospital, as wellas from the literature. For calculating the costsof the open surgery and EVAR procedures, themajor resources consumed were identified andthe costs calculated based on the average resourceuse reported in the literature. Fees for surgeonsand radiologists were derived from the Medicarereimbursement rates for the appropriate currentprocedural terminology codes. The immediate andlong-term costs of major long-term morbidities,such as stroke, dialysis-dependent renal failureand myocardial infarction, were derived fromthe literature. For EVAR rigorous postoperativesurveillance was also conducted, with CT scanningat 1 week, 3 and 6 months, 1 year and annuallythereafter. The study assumed that there wasno follow-up surveillance for those patients whounderwent open repair. Costs were discounted at arate of 3% per annum. Table 33 presents values forsome of the key cost parameters used in the model.TABLE 32 Key effectiveness parameters from Patel et al. 105Key parameters Value Source78EVAR operative mortality (%) 1.2 Average of three studies: Blum et al., 99 Goldstone et al., 100Zarins et al. 101Open repair operative mortality (%) 4.8 Johnston 102Conversion of EVAR to open repair duringprimary procedure (%)2.0 Weighted average of four studies: Blum et al., 99 Mialhe etal., 103 Jacobowitz et al., 104 Zarins et al. 101

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 33 Key resource cost parameters from Patel et al. 105Key resources Cost SourceInitial hospitalisation for EVAR procedure US$20,083 Assumptions and literatureInitial hospitalisation for open repair procedure US$16,016 Assumptions and literatureSummary of cost-effectivenessFor a hypothetical cohort of 70-year-old menwith an AAA of 5 cm in diameter, EVAR producedmore QALYs than open surgery (7.95 versus 7.53,respectively) at a higher lifetime cost (US$28,901versus US$19,314). This yielded an ICER ofUS$22,826 per QALY.A wide range of sensitivity analyses werealso undertaken. It was found that the ICERwas sensitive to changes in mortality andmorbidity rates of open surgery or EVAR, initialhospitalisation costs of EVAR or open surgery,and the conversion rate of EVAR to open repairduring primary procedure. For example, it wasfound that the mortality rate of open surgeryhad a large effect on the ICER, such that halvingthe mortality rate of open surgery from 4.8% to2.4% (and keeping the operative mortality rate ofEVAR constant) increased the ICER to US$43,408per QALY; similarly, if the mortality rate of theEVAR procedure was doubled from 1.2% to 2.4%(keeping the operative mortality rate of openrepair constant) the ICER increased to US$30,064per QALY.Table 34 presents ICERs for the base case and someof the sensitivity analyses performed in the study.CommentsGeneralPatel et al. 105 have found that under their base-caseassumptions EVAR is a cost-effective alternativeto open repair in 70-year-old men with an AAA of5 cm in diameter.Internal validityThe largest concern with the Patel et al. study is thatit is based on non-randomised data (as the studypredates the publication of the randomised trials),which raises immediate issues over the accuracy ofthe parameter estimates because of selection bias.External validityThere are a number of concerns with the Patel etal. study that raise questions over the relevanceof the results for the UK setting. First, the studyis US based and also dated (it was published in1999). Second, the study makes a large numberof assumptions that are not supported byevidence provided by the subsequent RCTs (ofwhich the results, it should be noted, were notavailable at the time). For example, the RCTsfound no evidence that the occurrence of strokeor myocardial infarction is different between thetreatment groups, 43 but Patel et al. have assumedthat it was lower after EVAR, which is one factorcausing the results to be in favour of EVAR. Third,the methods used to account for disutility in theimmediate aftermath of the initial procedure willbias against open repair when compared with otherstudies because of the longer relative period ofpost-intervention disutility assumed in the openrepair arm compared with the EVAR arm than inother studies (the study assumes a loss of 47 daysof perfect health for open repair, but a loss of onlyTABLE 34 Key cost-effectiveness results from Patel et al. 105ScenarioBase caseDiscounted incremental QALYs generated by EVAR compared with open repairDiscounted incremental cost of EVAR compared with open repairSensitivity analyses/alternate assumptionsOpen repair mortality rate 2.4% instead of 4.2%Increase in initial hospitalisation costs of EVAR to US$30,000Increase in rate of conversion of EVAR to open repair during primary procedure from 2% to15%© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.ICERUS$22,836 per QALY0.42 QALYsUS$9587US$43,408 per QALYUS$48,046 per QALYUS$50,944 per QALY79

Assessment of cost-effectiveness evidence11 days of perfect health for EVAR). Subsequentstudies, which are discussed at length later in thischapter, found that patients in both arms return tofull health within 3 months of either EVAR or openrepair. 106,107 There are also concerns about whetherthe HRQoL scores are comparable to those used inother studies, and whether they are appropriate forthe UK.It should also be noted that Patel et al. areevaluating the treatments in a patient populationhaving AAAs of a diameter of 5 cm, which is smallerthan that recommended by current guidelines (seeChapter 3).Bosch et al. Abdominal aorticaneurysms: cost-effectiveness of electiveendovascular and open surgical repair 108OverviewBosch et al. 108 performed a cost–utility analysiscomparing lifetime costs and QALYs for treatmentwith EVAR or treatment with open repair. The aimof the study was to evaluate the cost-effectiveness ofEVAR compared with open repair.The authors developed a Markov decision modelcomparing lifetime costs and QALYs for EVARand open repair in a cohort of 70-year-old menwith AAAs of between 5 and 6 cm in diameter.The clinical effectiveness data for the study werederived from the published literature, which at thetime did not include the two largest RCTs (EVARtrial 1 43 and DREAM 40 ). The authors focused onstudies with large patient series and cases of bothEVAR and open surgery. Resource use and costestimates were derived from various sources, whichwill be discussed further.Figure 64 provides a schematic of the model usedby the authors.Summary of effectiveness dataBecause of the lack of RCTs a meta-analysis of theshort-term results of studies comparing patientswho underwent EVAR with matched patientswho underwent open surgery was undertaken.The meta-analysis allowed calculation of theoperative mortality rates for each procedure aswell as the rates of complications in the short term(however, it is unclear from the study what timeperiod is considered the short term). The metaanalysisfound that the most commonly reportedsystemic and remote complications at 30 dayswere cardiac, cerebral, renal and pulmonary. Itwas assumed that these complications had a longtermeffect, which resulted in decreased HRQoLand added long-term costs. They estimated thatthe probability of systemic/remote complicationswas considerably lower with EVAR than with opensurgery (a probability of 0.13 for EVAR versus 0.32for open repair). Following the initial treatmentperiod no new systemic complications could occurexcept when a patient underwent emergent surgicalrepair. In the long term an annual average rupturerate of 0.01 for EVAR was used, with no ruptureafter open repair; for long-term reinterventiona rate of 0.08 per year was used for EVAR and0.01 per year for open surgery. Long-term lifeexpectancy was calculated based on age- and sexspecificmortality rates from life tables for the USgeneral population; however, this would seeminappropriate given the general ill health of thepatient population being considered. For patientswith major systemic complications, survival wasadjusted with an excess mortality rate.Quality of life weights before treatment and afterrecovery from either treatment were set similar tothose in the general population. To show the effectthat the treatments had in the short term on qualityof life, a 10% reduction in the first month followingEVAR was assumed, and a 30% reduction for 2months following open surgery was assumed. Longtermquality of life adjustments were also made forpatients with cardiac, cerebral, renal or pulmonarycomplications. QALYs were discounted at a rate of3% per annum.Table 35 presents values for some of the keyparameters used by the authors.Summary of resourceutilisation and cost dataThe authors included costs for procedures(including patient time productivity costs),morbidity and mortality, and imaging in follow-up.All costs were converted to year 2000 US dollars.Procedure costs included those of the hospital,physician and patient for EVAR, open surgery,percutaneous treatment and emergent surgicalrepair of rupture. The hospital cost and physicianfees were derived from Medicare reimbursementrates by using diagnosis-related groups. Patientcosts were determined by multiplying the dailywage rate by the number of days spent in hospital.It should be noted that when considering patient80FIGURE 64 Schematic of model from Bosch et al. 108 (Commercial-in-confidence information has been removed.)

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 35 Key effectiveness parameters from Bosch et al. 108Key parameters Value SourceMortality of open repair (%) 4.0 Meta-analysis of nine studies 109–117Mortality of primary EVAR (%) 3.0 Meta-analysis of nine studies 109–117Probability of immediate conversion after EVAR 3.0 Meta-analysis of nine studies 109–117Annual rupture risk after EVAR (%) 1.0 Harris et al., 118 Zarins et al. 119Annual long-term failure rate of EVAR, excluding ruptures, requiring 8.0 Zarins et al. 119treatmentAnnual long-term failure rate of open repair requiring treatment 1.0 Hallet et al. 120costs the authors of the study do not appear tohave accounted for other sick days that did notinvolve hospital stays. For costs for morbidity andmortality, if a major systemic/remote complicationoccurred during surgery then extra costs wereadded to the procedure costs. Costs of followupincluded physician visit costs, imaging costsand patient costs. In the model, patients whounderwent EVAR were imaged at 3, 6 and 12months, and annually thereafter. All costs werediscounted at 3%. Table 36 presents some of the keyresource costs used in the model.Summary of cost-effectivenessIn the base case it was found that EVAR resulted inmore QALYs than open repair (6.74 versus 6.52,respectively) and also more costs (US$39,785 versusUS$37,606, respectively), resulting in an ICER ofUS$9905 per QALY. A wide range of sensitivityanalyses, including both one- and two-way analyses,were also performed. These found that the resultswere highly sensitive to the uncertain parametersin the model, such as the systemic complicationrate, long-term failure rate and rupture rate. Forexample, if the annual rate for procedures infollow-up in the EVAR arm was increased from 8%to 12% then the ICER increased to US$56,630 perQALY, and if the rate exceeded 12% then the ICERwas more than US$100,000 per QALY. Table 37presents the ICERs for the base case and for someof the sensitivity analyses performed in the study.CommentsGeneralThe authors of this study have found that, giventypical thresholds, EVAR is likely to be consideredcost-effective compared with open repair in70-year-old men with AAAs of between 5 cm and6 cm in diameter.TABLE 36 Key resource cost parameters from Bosch et al. 108Key resources Cost SourceEndovascular repair procedure US$19,642 MedicareOpen repair procedure US$23,484 MedicareFollow-up imaging (per visit) US$483 MedicareTABLE 37 Key cost-effectiveness results from Bosch et al. 108ScenarioBase caseDiscounted incremental QALYs generated by EVAROverall incremental cost of EVAR arm compared with open repair armSensitivity analyses/alternative assumptionsAnnual rate for procedures in follow-up after EVAR increased from 8% to 12%Annual long-term failure rate after open surgery decreased from 1% to 0.5%© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.ICERUS$9905 per QALY0.22 QALYsUS$179US$56,630 per QALYUS$54,233 per QALY81

Assessment of cost-effectiveness evidence82Internal validityThere are a number of issues with the Bosch et al.study that may have led to the results producedbeing inaccurate. First, the fact that the valuesused for the parameters in the model are notbased on RCT evidence (as the study predates thesubsequent trials) is clearly a major weakness andraises doubts about their relevance. Second, inthe absence of better data, the authors have beenforced to make a large number of assumptions(e.g. about recovery time, cost of mortality, qualityof life, number and type of additional proceduresperformed, etc.), thus limiting the robustness ofthe results. The authors state that the sensitivityanalyses conducted test these assumptions andevaluate the influence that any uncertainty in theseassumptions may have on the base-case ICER.However, as only one- and two-way sensitivityanalyses were conducted and the results werenot all presented, the authors are unlikely tohave accurately captured the uncertainty in theirassumptions.External validityThere are several issues with the Bosch et al. studybeyond those described above that may limitthe transferability of the results to a UK setting.First, the inclusion of patient costs (productivitycosts) may mean that the results of this study aredifficult to compare with those of other studiesthat do not include patient costs in their resourceuse estimates. Second, it should also be noted thatthe study includes patients with AAAs of between5 cm and 5.5 cm in diameter. Such patients wouldnot currently be considered for surgery in theUK, where only patients with AAAs of > 5.5 cmin diameter are considered for surgery. Third, asthe results are based on a US population in a UShealth-care setting, they may not be transferableto the UK because of the differences in the patientpopulation and resource use.Michaels et al. Cost-effectivenessof endovascular abdominalaortic aneurysm repair 107OverviewThis study evaluated the cost-effectiveness of EVARcompared with open repair in patients fit forsurgery (RC1) or with conservative managementin those unfit for surgery (RC2) (this section of thestudy will be discussed later in this chapter; seeCost-effectiveness studies focusing on the EVARtype 2 population). The aim of the study was todetermine an optimal strategy for the use of EVARbased on the best available evidence at the time.Effectiveness and resource use data were basedon recent RCTs (EVAR trial 1 42 and DREAM 40 ) aswell as on a systematic review of the literature. Thestudy was conducted after the short-term (30-day)operative mortality results were published fromthese trials but before the mid-term results wereavailable. The authors developed a Markov modeland used it to consider two separate ‘referencecases’, one of which was similar to the EVAR trial1 population. They considered fit 70-year-oldpatients with an AAA of 5.5 cm in diameter forwhich the choice of treatment was between EVARand open surgery (RC1). The primary outcomemeasure for the cost-effectiveness analysis was theincremental cost per QALY gained. The authorsused a 10-year time horizon. The evaluation wasundertaken from the perspective of the NHS.Figure 65 represents the Markov decision model forRC1.Summary of effectiveness dataShort-term operative mortality probabilitieswere taken from the EVAR trial 1 42 and DREAMtrial. 40 The probabilities of reintervention andcomplications were derived from a previouslyconducted systematic review. General mortalitywas taken from standardised mortality tables forEngland and Wales (it should be noted that it isnot stated whether these have been adjusted forthe poorer health of patients with aneurysms).Aneurysm-related mortality was calculated from aprevious modelling study.Utility estimates were based on published figuresderived from the EQ-5D tariff values for men aged65–74 years. To account for the lower HRQoLinitially following surgery, a reduction in keepingwith that seen after major surgery was applied forthe first 4 weeks after open surgery and for the first2 weeks after EVAR. QALYs were discounted at arate of 3.5% per annum.The key effectiveness parameters for the model arereported in Table 38.Summary of resourceutilisation and cost dataMost costs were based on NHS reference costsfor 2003–4 123 with the mean cost being thepoint estimate. For the probabilistic sensitivityanalysis a normal distribution was assumed withstandard deviation based on the assumption that50% of observations were within the publishedinterquartile range. The additional incrementalcost of EVAR was estimated from data collected

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48SurgeryContinued survivalAneurysm-related deathLiveDieContinued survivalDeathDeathChoosetreatmentEVARSuccessful open repairExcludedEndoleakReinterventionDeathLiveDieReinterventionRemain excludedDevelop leakAneurysm-related deathDieEndoleak exclusionPersistent endoleakEndoleak reinterventionAneurysm-related deathDieOpen conversionReintervention successfulFailed interventionDie other causesSuccessful open repairDeathReinterventionExcludedEndoleakAneurysm-related deathDeathExcludedEndoleakReinterventionAneurysm-related deathDeathSuccessSuccessful open repairDieAneurysm-related deathExcludedEndoleakDeathAneurysm-related deathFIGURE 65 Schematic of model from Michaels et al. 107 © British Journal of Surgery Society Ltd. Reproduced with permission, grantedby John Wiley & Sons on behalf of the BJSS Ltd.TABLE 38 Key effectiveness parameters from Michaels et al. 107Key parameters Value SourceMortality of open repair (%) 5.80 EVAR trial 1 42 and DREAM 40Mortality of primary EVAR in initial 1-month period (%) 1.85 EVAR trial 1 42 and DREAM 40Probability of conversion of EVAR to open repair during 1.90 Drury et al. 121primary procedure (%)Utility for living patient following treatment 0.8 Health Survey for England 1996 122at the Sheffield Teaching Hospital NHS Trust.Follow-up costs for EVAR were based on NHSreference costs with the assumption that on averagean EVAR patient will have two outpatient visitsand two CT scans per year. After open repair theaverage cost of a reintervention in the EVAR armagain used NHS reference costs 123 but was basedon the case mix of reinterventions as recorded inthe EUROSTAR registry. 124 All costs have beendiscounted at a rate of 3.5% per annum. Thekey resource cost parameters for the model arereported in Table 39.83© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 39 Key resource cost parameters from Michaels et al. 107Key resources Cost SourceCost of open AAA repair £4269 NHS reference costs 123Cost of EVAR repair £8769 Sheffield Teaching Hospital NHS TrustEVAR follow-up cost per month £41.50 NHS reference costs 123Reintervention £4790 NHS reference costs 123 and EUROSTAR 124Summary of cost-effectivenessRC1 reference caseThe base-case results for RC1 showed thatEVAR resulted in increased QALYs (0.1 QALYs)compared with open surgery but also increasedcosts (£11,449), resulting in an ICER of £110,000per QALY.A variety of univariate sensitivity analyses wasalso undertaken, such as changing the initialincremental cost of the EVAR procedure, alteringthe discount rate, changing the time horizon, usingmortality rates from the systematic review insteadof the clinical trials and altering the reinterventionrate. The ICER was as low as £53,773 per QALYwhen the initial incremental cost of EVARcompared with open surgery was reduced to £0and as high as £144,552 when the time horizonwas increased to 15 years. When the mortality rateswere taken from the review instead of the trials,EVAR was dominated by open surgery.Michaels et al. also undertook a probabilisticsensitivity analysis. All of the simulations generatedan ICER of greater than £30,000 per QALY (i.e.the probability of the ICER being less than £30,000per QALY was zero).Table 40 presents the ICERs for the RC1 basecase as well as for some of the sensitivity analysesconducted.CommentsGeneralMichaels et al. found that EVAR does not appear tobe cost-effective in an EVAR trial 1-type patient (i.e.RC1 in their analysis). This is because of the highincremental cost and low incremental effectivenessof EVAR compared with open surgery.Internal validityShort-term operative mortality rates in theMichaels et al. study are based on RCT evidence.However, as this study was conducted beforemid-term results from the RCTs were available,longer-term probabilities are based on the resultsof a review of the literature 121 and have not beenderived from RCTs. As such they are open to biasand may not accurately reflect those of the patientpopulation being considered.The study in the base case also only considers atime horizon of 10 years (although this is extendedto 15 years in sensitivity analysis). This may not belong enough to capture all of the cost and outcomedifferences between the two trial arms.External validityThe study is UK based and has been conductedfrom the perspective of the NHS. However, asnoted above, not all of the parameters have beenestimated from RCTs and are thus open to bias.TABLE 40 Key cost-effectiveness results from Michaels et al. (RC1) 107ScenarioICERBase case£110,000 per QALYDiscounted incremental QALYs generated by EVAR (RC1) 0.10Discounted incremental cost of EVAR patient compared with open repair patient (RC1) £11,44984Sensitivity analyses/alternative assumptionsIncremental cost of initial EVAR procedure £015-year time horizon£53,773 per QALY£144,552 per QALY

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Epstein et al. Modelling the long-termcost-effectiveness of endovascular or openrepair for abdominal aortic aneurysm 106OverviewThe study evaluated the cost-effectiveness ofEVAR compared with open surgery in a patientpopulation of 74-year-old men with a diagnosedAAA of diameter ≥ 5.5 cm. It should be noted thatseveral of the authors of this report were authors ofthis study.The authors constructed a Markov decisionmodel to estimate the lifetime costs and QALYsof male patients aged 74 years with an AAA ofdiameter ≥ 5.5 cm. Effectiveness and resource usedata used to populate the Markov model werelargely drawn from an RCT, EVAR trial 1. Themodel includes the risks of death from aneurysmand other cardiovascular and non-cardiovascularcauses, secondary reinterventions and non-fatalcardiovascular events.ICERs were reported for the base case as well as fora number of sensitivity analyses (e.g. for differentstarting ages). The probability that EVAR is costeffectiveat a threshold of £20,000 per QALY and£40,000 per QALY was also reported, based onprobabilistic sensitivity analyses.Figure 66 provides a schematic of the model used inthe study.Summary of effectiveness dataThe effectiveness data were largely taken fromEVAR trial 1 although this has been supplementedby other data sources. Mortality from the initialprocedure was calculated from EVAR trial 1. Itwas assumed that if an EVAR patient converted toopen repair during the primary admission thenthey would have the same long-term prognosis asan individual who had originally been allocated toEVAR. Mortality rates after the initial admissionwere estimated as three competing risks: (1) deathfrom an AAA cause, (2) death from a cardiovascularcause other than AAA and (3) death from a noncardiovascularcause. Patients were also at risk ofa non-fatal cardiovascular event or a readmissionfor a second AAA procedure, all of which wereassociated with higher costs and lower utilities.The model assumed that the initial operativemortality benefit of EVAR compared with openrepair was eroded after 2 years by additional deathsfrom cardiovascular causes after EVAR, based onthe results of EVAR trial 1 and the DREAM trialshowing that there was no difference in mid-termsurvival between the treatments. The model alsoassumed that there would be a small but persistentdifference in late aneurysm-related deaths betweenthe treatments.It has been assumed that the baseline utility ofthese patients is the same as that of the age-specificUK general population estimates. There is aninitial loss of utility for 1 month post surgery withopen repair resulting in a larger loss (a reductionof 0.094 compared with 0.027 for EVAR). 43 Thereis also a 1-month loss of utility for a non-disablingstroke or myocardial infarction, and a permanentutility decrease following a disabling stroke. In thebase case all QALYs were discounted at a rate of3.5% per annum.Table 41 provides a summary of some of the keyeffectiveness parameters used in the model.Conversion toopen repairS2MainadmissionNon-fatalstroke or MISymptom-freesurvivalNon-fatalsecondaryreadmissionDeathS1FIGURE 66 Schematic of model from Epstein et al. 106 © British Journal of Surgery Society Ltd. Reproduced with permission, granted byJohn Wiley & Sons on behalf of the BJSS Ltd.85© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 41 Key effectiveness parameters from Epstein et al. 106Key parameters Value SourceProbability of operative (30-day) mortality for EVAR (%) 5.0 EVAR trial 1 43Probability of operative (30-day) mortality for open repair(%)Probability of conversion to open repair from EVAR duringprimary admission (%)Mortality rate from AAA-related causes during follow-up withEVARMortality rate from AAA-related causes during follow-up withopen repair1.6 EVAR trial 1 430.8 EVAR trial 1 436 per 15,000 patient-months,assumed constant over patient’slifetime1 per 15,000 patient-months,assumed constant over patient’slifetimeEVAR trial 1 43EVAR trial 1 43Summary of resourceutilisation and cost dataResource utilisation and cost data for the initialEVAR or open repair surgery, a conversion to openrepair during primary EVAR, and a secondaryreadmission for an AAA have all been taken fromthe EVAR trial. Costs for non-fatal cardiovascularevents have been taken from Jones et al. 125All patients in the EVAR group have been assumedto require hospital outpatient attendances and CTto monitor their aneurysm repair. In the base caseit was assumed that two surveillance visits wouldbe required in the first year and then one annuallythereafter. The costs for these visits and scans havebeen taken from NHS reference costs. 123 In the basecase all costs were discounted at a rate of 3.5% perannum. Table 42 summarises some of the key costparameters used by the authors in the model.Summary of cost-effectivenessIn the base case EVAR was more costly than openrepair by £3800 per patient but also producedfewer lifetime QALYs than open repair (mean–0.020 QALYs). Therefore, under the base-caseassumptions EVAR was dominated by open repair.The base-case assumptions were varied in aseries of secondary analyses to reflect alternativeevidence and opinions about some of the keyparameters in the model. In only one case wasthe EVAR ICER found to be under £30,000 perQALY. This occurred when the age of the initialcohort was increased from 74 to 82 years (with agreater absolute difference in operative mortalitybetween the treatments) and the lower long-termrate of cardiovascular death after open surgerywas replaced with the assumption that there is nodifference in the rate of cardiovascular death afteropen repair or EVAR.ICERs for the base case and some of the sensitivityanalyses conducted are presented in Table 43.CommentsGeneralEpstein et al. found that EVAR was not a costeffectiveuse of resources in 74-year-old malepatients with an AAA of diameter ≥ 5.5 cm. Undertheir base-case assumptions they found that EVARwas dominated by open repair (i.e. it had highercosts but worse outcomes).Internal validityThe authors of this study have used RCT evidenceto parameterise this model, which is the mostpreferred form of evidence according to NICE. 15However, they have still had to make assumptions,TABLE 42 Key resource cost parameters from Epstein et al. 106Key resources Cost Source86EVAR procedure £10,726 EVAR trial 1 43Open repair procedure £9578 EVAR trial 1 43Conversion to open repair during primary EVAR £42,067 EVAR trial 1 43

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 43 Key cost-effectiveness results from Epstein et al. 106ScenarioICERBase caseEVAR dominatedDiscounted incremental QALYs generated by EVAR–0.020 QALYsDiscounted incremental cost of EVAR arm compared with open repair arm £3578Sensitivity analyses/alternative assumptionsAge 82 years and no difference in rate of cardiovascular death after open repair orEVARSame hazard of cardiovascular death following each treatment strategyNo difference between EVAR and open repair in the long-term rate of AAArelateddeath£27,000 per QALY£42,000 per QALY£42,000 per QALYparticularly for the rates of cardiovascular deathsand non-fatal events in the medium term.Assumptions were also made about values ofparameters after 4 years as this is the maximumlength of follow-up that was available from theEVAR trial. If these assumptions do not hold thenthe accuracy of the results will be questionable.External validityEpstein et al. have conducted the results from theperspective of the NHS. This is the appropriateperspective for NICE to make decisions. However,as noted in the internal validity section, if anyof the assumptions made do not hold then therelevance of the results to the NHS may be inquestion. Some data from EVAR trial 1, particularlyregarding procedure costs and long-termreintervention rates of current devices, may bedated.Prinssen et al. Cost-effectivenessof conventional and endovascularrepair of abdominal aortic aneurysms:results of a randomized trial 126OverviewThe authors conducted a cost-effectivenessanalysis of a multicentre randomised trial of EVARcompared with open repair in patients with AAAsof ≥5 cm in diameter. The analysis is conducted forup to 1 year after the original procedure. All of theeffectiveness and resource use data were taken fromthe DREAM trial (therefore relevant data fromEVAR trial 1 has been excluded).Summary of effectiveness dataHRQoL was assessed using the EQ-5Dquestionnaire. Questionnaires were filled in by thetrial patients at baseline (upon randomisation)and at 3 and 6 weeks and 3, 6 and 12 monthspostoperatively. By using linear interpolation forperiods between measurements, quality-adjustedsurvival time was calculated up to 1 year afterinclusion. A small and non-significant benefit ofopen repair compared with EVAR was found. Table44 summarises the QALY outcomes from the twotrial arms over a 1-year period.Summary of resourceutilisation and cost dataCosts associated with treatment and followupuntil 1 year after inclusion were calculatedby multiplying individual patient resource userecorded in the trial by unit costs. All costs werecalculated in 2003 euros.The costs of lost productivity were also calculated.These took account of sick leave and travel, as wellas other costs incurred by the patients and theirfamilies. Table 45 summarises the average total costin each trial arm based on a bootstrap estimate.TABLE 44 Key effectiveness parameters from Prinssen et al. 126Key parameters Value SourceQALYs generated by EVAR over 1 year 0.72 QALYs DREAM 126QALYs generated by open repair over 1 year 0.73 QALYs DREAM 12687© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 45 Key resource cost parameters from Prinssen et al. 126Key resource Cost SourceAverage total cost of EVAR patient (from bootstrap) €18,179 DREAM 126Average total cost of open repair patient (from bootstrap) €13,886 DREAM 126Summary of cost-effectivenessThe authors found that patients in the EVAR groupexperienced less QALYs than those in the openrepair group (0.72 QALYs versus 0.73, respectively)whilst incurring more costs (€18,179 versus€13,886, respectively). Thus, EVAR was dominatedby open repair with a 1-year time horizon.The authors also conducted a non-parametricbootstrapping approach to evaluate the jointuncertainty in outcomes and costs.Table 46 presents the key cost-effectiveness resultsfor the study.CommentsGeneralThe authors of this study have found that, with a1-year time horizon, EVAR is dominated (it hashigher costs and lower effectiveness) by open repairin patients with an AAA of diameter ≥ 5 cm insize. It should be noted that this inclusion criteriais different to that in EVAR trial 1 in which onlypatients with an AAA of ≥ 5.5 cm in diameter wereincluded.Internal validityThe approach taken by the authors of this studyraises issues about the validity of the resultsproduced. Most importantly, the short timehorizon means that any differences between armspost 1 year have not been captured and these maybe important when determining cost-effectiveness.For example, given that mortality was higher inthe open repair arm than in the EVAR arm, bynot extrapolating results the authors may havebiased their results against the EVAR arm by notaccounting for the fact that there are more patientsstill alive at 1 year in this arm and thus morepatients who can accrue QALYs over time. Theyhave also ignored differences in complications andmortality that arise after 1 year.External validityThe study is a Dutch study and as such the resultsmay not be transferable to an NHS setting. Theinclusion of patient costs is also not relevant forNICE decision-making; however, if anything thiswould be expected to bias the results against openrepair because of the observed longer recovery timeafter the initial procedure in this arm.Medtronic submission. Endovascularaneurysm repair (EVAR) for thetreatment of infra-renal abdominalaortic aneurysms (AAA) 127OverviewIn this study the authors conducted a cost–utilityanalysis comparing EVAR with open repair. Thepatient population considered was that of EVARtrial 1, i.e. patients with an unruptured infrarenalAAA of at least 5.5 cm in diameter who areconsidered fit for open surgery. The average ageof the population was 70 years and 90% of patientswere men.The authors developed a two-stage model toestimate the lifetime costs and QALYs of EVARTABLE 46 Key cost-effectiveness results from Prinssen et al. 12688VariableEstimateTotal average cost of EVAR patient over 1 year €18,595Total average cost of EVAR patient over 1 year (bootstrapped) €18,179Total average cost of open repair patient over 1 year €13,627Total average cost of open repair patient over 1 year (bootstrapped) €13,886Average QALYs generated by EVAR patient0.72 QALYsAverage QALYs generated by open repair patient0.73 QALYs

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48and open repair in this patient population: first,a decision tree for the first 30 days post surgery;second, a Markov model from 30 days post surgeryuntil death.Figure 67 represents the short-term decision treefor the first 30 days post surgery. At the end of thefirst 30 days patients in the EVAR arm will endup in one of four states: (1) successful EVAR withno complications, (2) EVAR with complications,(3) conversion to open surgery or (4) death.Conversely, those in the open repair arm initiallymay end up in one of three states: (1) open repairwith no complications, (2) open repair withcomplications or (3) death.Once patients enter the 30 days post surgeryMarkov model (Figure 68) then they must be in oneof four health states: (1) no complications requiringsecondary intervention, (2) technical complicationsrequiring secondary intervention, (3) systemiccomplications (split into a first-year phase and thensubsequent years phase) or (4) death.Summary of effectiveness dataThe effectiveness data used to parameterise themodel were largely drawn from EVAR trial 1 43but were supplemented with data from additionalsources.For the short-term model, mortality estimates andthe need for secondary intervention were basedon data from EVAR trial 1. However, the risk ofconversion from EVAR to open surgery was basedon clinical expert opinion rather than on thetrial (the authors used a probability of conversionAliveNo conversionNo complicationsComplicationsMMAAAEVARDeathDeathConversion to OSRMOSRAliveComplicationsNo complicationsMMFIGURE 67 Schematic of decision tree from Medtronic submission, 127 reproduced with permission from Medtronic.Enter fromdecisionSystemiccomplicationsNo complicationsrequiring secondaryinterventionTechnicalcomplicationsDeathFIGURE 68 Schematic of Markov model from Medtronic submission, 127 reproduced with permission from Medtronic.89© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceof 0.2%, which is much lower than that used inother studies, e.g. Epstein et al., 106 in which theprobability was four times larger at 0.8%, takenfrom EVAR trial 1 43 ).The baseline risk of systemic complications(myocardial infarction, temporary and permanentrenal failure, and disabling and non-disablingstroke) for EVAR patients in the first 30 days wasestimated from the EUROSTAR data set. Therelative risk of systemic complications for opensurgery versus EVAR was taken from a metaanalysisof observational studies and one RCT(DREAM). The authors have assumed that theincidence rates for systemic complications followthe same pattern as for all-cause mortality, i.e. thatopen repair patients have a higher incidence in thefirst 30 days post surgery whereas EVAR patientshave a higher incidence from 30 days to 18 monthspost surgery. Therefore, it has been assumed thatover the first 18 months the number of events thatoccur in the two groups is equal. The authors haveachieved this in the model by using the incidencerate of myocardial infarction and stroke in thegeneral UK population for the open repair groupfrom 30 days to 18 months. Then the relative riskfor EVAR was calculated such that the numberof events was equal at 18 months. However, itshould be noted that the numbers of events ineach arm were only equal for myocardial infarctionand stroke and not for renal failure. This wasconsidered to be closely related to the interventionitself and therefore could only occur in the first 30days, hence there was a higher prevalence of renalfailure in the open repair arm. The authors havethen assumed that no new systemic complicationsoccur from 18 months onwards.Long-term risks of mortality and secondaryinterventions were also based on data from EVARtrial 1. 43 The authors considered two scenarios forestimating the difference in late mortality (after30 days). First, they considered a relative risk forEVAR compared with open repair for late mortality(for any cause) of 1.055, applied for 4 years. Theauthors stated that this relative risk was calculatedfrom EVAR trial 1 but it was not clear exactly howthis was carried out. In the second scenario thedifference in mortality between the two treatmentsis only due to AAA mortality, and the authorsestimate a relative risk of 1.18, again based onEVAR trial 1 results for late aneurysm mortality. Itshould be noted that EVAR trial 1 reported HRs(EVAR relative to open surgery) for aneurysmrelatedmortality of 0.42 (95% CI 0.21 to 0.82) forthe first 6 months and 1.15 (95% CI 0.39 to 3.41)from 6 months to 4 years; the corresponding HRsfor total mortality in the two periods were 0.55(95% CI 0.33 to 0.93) and 1.10 (95% CI 0.80 to1.52) respectively. The authors assumed that from1 month post surgery until 4 years the patientsexperience this as a constant relative risk of death.At 4 years it has been assumed that patientsin both arms experience a risk of death that issimilar to that of the background UK populationwith adjustments for increased incidence ofcardiovascular death in an AAA population aftersurgery.The risk of patients requiring a secondaryintervention was derived from EVAR trial 1 andthen supplemented with data from other sources.The total number of secondary interventionswas taken from the EVAR trial; the secondaryintervention rate was 1.72% per month from 2 to 6months post surgery in the EVAR arm and 1.03%in the open repair arm, whereas for post 6 monthsthe rate in the EVAR arm was 0.27% and therewere no secondary interventions post 6 monthsin the open repair arm. The percentages of thesesecondary interventions that were transabdominal,extra-anatomic or transfemoral has then beenderived from other sources, notably EUROSTARfor the EVAR group and expert clinical opinion forthe open repair group. Both patient groups havea constant risk of secondary intervention from theoperation until 6 months post operation. Post 6months it is assumed that open repair patients areno longer at risk of secondary interventions andthat the rate of reintervention for EVAR patientsremains constant over time. The authors have alsoassumed that patients do not experience disutilityfrom secondary interventions and that they havethe same prognosis as other patients after thereintervention.Utility scores for health states have been takendirectly from EVAR trial 1. In the first 3 monthspost surgery, those in the open repair arm hada lower utility than those in the EVAR arm (0.67versus 0.73). From 24 months onwards it wasassumed that utility was equal in both arms(although it was age dependent). Disutility scoresfor the systemic complications have been drawnfrom several sources.Table 47 presents the values used for some of thekey parameters in the model.90

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 47 Key effectiveness parameters from Medtronic submission 127Key parameters Value SourceMortality of open repair (%) 4.19 Brown et al. 23Mortality of primary EVAR (%) 1.62 Brown et al. 23Probability of conversion of EVAR to open repair (%) 0.2 Brown et al. 23 and expert opinionMortality all-cause (monthly) – EVAR 0.48% EVAR trial 1 43Mortality all-cause (monthly) – open repair 0.46% EVAR trial 1 43Mortality AAA-related (monthly) – EVAR 0.035% EVAR trial 1 43Mortality AAA-related (monthly) – open repair 0.034% EVAR trial 1 43Summary of resourceutilisation and cost data(Commercial-in-confidence information has beenremoved.)The authors also assumed that 50% of follow-upscans are now duplex ultrasound and 50% are CT,with the same frequency of monitoring as in theEVAR trial 1 protocol. As duplex ultrasound ischeaper than CT this reduced the overall cost ofmonitoring in the EVAR arm.The costs for secondary interventions were drawnfrom NHS reference costs. 123 The costs for thesame type of intervention (e.g. transabdominalintervention) are assumed to be the same foreach treatment arm. However, the percentage ofeach type of intervention as a proportion of thetotal number of secondary interventions differsbetween the two treatments, with open repairhaving the highest proportion of the most costlyprocedures, making the average cost per secondaryintervention higher in the open repair group.These percentages are not based on trial evidencebut instead on the EUROSTAR registry in the caseof the EVAR arm and on clinical opinion in thecase of the open surgery arm. Table 48 presentssome of the values used for key cost parameters inthe model.Summary of cost-effectivenessThe authors found that in the base case patientstreated with EVAR were expected to receive moreQALYs than those treated with open surgerybut at a higher cost (commercial-in-confidenceinformation has been removed). This resulted inan ICER of £15,681 per QALY for EVAR comparedwith open repair.The authors also conducted univariate sensitivityanalyses for all of the parameters in the model,using the values for the lower and upperconfidence limits of each parameter. They foundthat the ICER was most sensitive to the short-termrelative risk of operative mortality.Table 49 presents ICERs for the base case and thesensitivity analysis in which the short-term relativerisk of mortality was varied.CommentsGeneralThe authors of this study have found that, undertheir base-case assumptions, EVAR is a costeffectiveuse of resources compared with opensurgery in the EVAR trial 1 patient population(i.e. patients with an average age of 70 years, 90%of whom are men, and with an AAA of at least5.5 cm in diameter) assuming a cost-effectivenessthreshold of £20,000 per QALY.TABLE 48 Key resource cost parameters from Medtronic submission 127Key resources Cost SourceCost of open AAA repair (CiC information has been removed) EVAR trial 1 43Cost of EVAR repair (CiC information has been removed) Medtronic 127CiC, commercial-in-confidence.91© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 49 Key cost-effectiveness results from Medtronic submission 127ScenarioBase caseDiscounted incremental QALYs generated by EVARDiscounted incremental cost of EVAR patient compared with open repair patientSensitivity analyses/alternative assumptionsLower confidence limit for short-term relative risk of mortality [CiC informationhas been removed]Upper confidence limit for short-term relative risk of mortality [CiC informationhas been removed]ICER(CiC information has been removed)(CiC information has been removed)(CiC information has been removed)(CiC information has been removed)(CiC information has been removed)CiC, commercial-in-confidence.92Internal validityThe first issue relates to assumptions made aboutthe rate of systemic complications (renal, cardiacand cerebrovascular events). In particular, theMedtronic analysis assumed that no new systemiccomplications occurred after 18 months; that therewere no new cases of renal failure after 30 days; andthat open repair patients have a higher incidenceof all systemic complications before 30 days butEVAR patients have a higher incidence from 1 to18 months such that they have equal incidenceat 18 months. To test whether these assumptionsaffected the results we conducted an additionalsensitivity analysis using the Excel model suppliedto us by Medtronic. We set the rates of renal failureand cardiovascular complications in the first 30days and in the long-term model to be the sameafter EVAR and open repair (ORs and HRs equal to1). We found that there was only a small difference(ICER £18,000 per QALY) compared with theMedtronic base case (commercial-in-confidenceinformation has been removed) and we concludethat these assumptions do not affect the overallconclusions of the Medtronic model.Second, the authors assume that there is nodisutility associated with secondary interventionsand no risk of perioperative complications. If theseassumptions do not hold then they will bias theresults in favour of EVAR being cost-effective, asEVAR has a higher rate of secondary interventions.Third, (commercial-in-confidence information hasbeen removed).Fourth, Medtronic also assume that a smalldifference in survival in favour of EVAR ismaintained over the patient’s lifetime (commercialin-confidenceinformation has been removed). Thismodel assumption is not supported by the resultsof the EVAR trial 1 and DREAM trials, which bothfound no difference in survival at 4 years.External validityIn addition to the key issues discussed above thereare other issues that may affect the validity ofthe results for the UK setting. (Commercial-inconfidenceinformation has been removed.)Bowen et al. Systematic reviewand cost-effectiveness analysisof elective endovascular repaircompared to open surgical repairof abdominal aortic aneurysms 128OverviewThe authors developed a decision-analytic modelto evaluate the costs and QALYs associated withEVAR and open surgical repair. The model relatesto 70-year-old male patients with AAAs of 5.5 cmdiameter who are considered medically suitableto undergo either open surgical repair or EVARover a period of 13 months. The first 30 days aremodelled using a decision tree and the following12 months are modelled using a Markov decisionmodel. The Markov models for the following 12months for those patients who received EVAR andthose patients undergoing open surgical repairwere similar, with conversion to open surgicalrepair and the endoleak states removed.Summary of effectiveness dataSeveral sources of data were used to parameterisethe model, including data from a non-randomisedfield evaluation conducted by the authors andresults from a systematic literature review. Most ofthe probabilities used in the model were derived

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 50 Key effectiveness parameters from Bowen et al. 128Key parameters Value SourceProbability of death immediately following EVAR (%) 2.6 Meta-analysisProbability of death immediately following open surgical repair (%) 4.3 Meta-analysisProbability of early conversion from EVAR to open surgical repair (%) 1.2 Meta-analysisUtility in first 30 days following EVAR 0.70 Field studyUtility in first 30 days following open surgical repair 0.56 Field studyUtility in first 90-day cycle following initial 30 days for EVAR 0.83 Field studyUtility in first 90-day cycle following initial 30 days for open surgical repair 0.67 Field studyUtility in second 90-day cycle following initial 30 days for EVAR 0.85 Field studyUtility in second 90-day cycle following initial 30 days for open surgical repair 0.77 Field studyUtility in fourth 90-day cycle following initial 30 days for EVAR 0.91 Field studyUtility in fourth 90-day cycle following initial 30 days for open surgical repair 0.91 Field studyfrom the literature review and meta-analyses. Theseincluded the EVAR 1 and DREAM trials as wellas other non-randomised sources. It should benoted that it is not clear which sources were usedfor the meta-analysis for probability of death. Allcausemortality was derived from the life tablesof Statistics Canada. The utility values assignedto different states in the model were based onadjusted estimates of the EQ-5D scores reported inthe field evaluation conducted by the authors.Table 50 presents some of the key effectivenessparameters from the study.Summary of resourceutilisation and cost dataData on costs and resource use were derivedfrom a variety of sources. The costs of the initialhospitalisation for each treatment arm werederived from the costs observed in the field studyconducted by the authors. This field study wasa non-randomised prospective study that aimedto compare EVAR patients at high risk for opensurgical repair with patients receiving open surgicalrepair with either low or high surgical risk. Thestudy prospectively collected clinical outcomes,resource utilisation data and quality of lifeinformation.Costs of major complications during initialhospitalisation (e.g. myocardial infarction, stroke,etc.) were based on mean hospital costs for eachcondition found in the Ontario Case CostingInitiative database. The 1-year follow-up costs forEVAR and open surgical repair were also derivedfrom the field study. Costs were also derived fromthe literature.The values for some key resource cost parametersare reported in Table 51.Summary of cost-effectivenessIn the base case EVAR was both more costly thanopen surgical repair (C$32,079 versus C$17,503)and more effective (0.863 QALYs versus 0.772QALYs) over a period of 13 months. As such theincremental cost per QALY was found by theauthors to be C$160,176 (Table 52). Because ofconcerns that the authors had over some of thenon-randomised results used from the systematicreview to parameterise the model, particularly withregards to complications, the authors performed asecondary analysis in which complication costs andrates were taken from the field study. Because ofthe low number of complications observed in theEVAR arm of the field study the ICER was lowerthan that found in the base case (C$22,528 perQALY versus C$160,176 per QALY; Table 52).TABLE 51 Key resource cost parameters from Bowen et al. 128Key resources Cost SourceHospitalisation for open surgical repair – no major complications C$13,243 Field studyHospitalisation for EVAR – no major complications C$23,525 Field study93© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 52 Key cost-effectiveness results from Bowen et al. 128ValueBase caseC$160,176 per QALYIncremental QALYs generated by EVAR 0.091Incremental cost of EVAR arm compared with open repair arm C$14,576ICER based on field evaluation complication rates and costsC$22,528 per QALY94CommentsGeneralBowen et al. found that in their base case EVAR didnot appear to be a cost-effective use of resources(with an ICER of C$160,176 per QALY). However,when results from their field study were used inplace of results from the literature review EVARappeared to be cost-effective assuming a thresholdof as low as C$23,000 per QALY.Internal validityThe use of non-randomised data in this study raisesissues about the internal validity of the resultsfor both the primary and secondary analyses.Although RCT data have been used (EVAR trial 1and DREAM), the authors have synthesised thesedata with data from non-randomised studies. Theauthors have also not conducted sensitivity analysesto test the robustness of their results to changes incertain parameters.External validityThe study is conducted from the perspective ofthe Canadian health-care system and as such itsapplicability to the UK NHS is unclear. The use ofnon-randomised data, which raises issues aroundthe internal validity of results, also affects theexternal validity of the results.Bowen et al. Systematic reviewand cost-effectiveness analysisof elective endovascular repaircompared to open surgical repairof abdominal aortic aneurysms 129OverviewA cost-effectiveness analysis was performed basedupon a field evaluation conducted by the authorsof this report. The analysis focused on high-riskpatients and had a time horizon of 1 year. As thisstudy only considers data from the authors’ nonrandomizedfield study and does not incorporateother evidence (e.g. from the available RCTs), itsrelevance to the UK is considered to be limited.Therefore, only a brief review of the study ispresented here.Summary of effectiveness dataThe authors estimated the life-years gained over 1year using results from the field study and Kaplan–Meier survival curves. The life-years were thenconverted into QALYs by combining the survivalcurves with utility estimates, also derived from thefield study, over time.The authors also conducted sensitivity analysis onthe time horizon considered in the study usingseveral assumptions regarding the extrapolationof survival curves (no convergence, convergenceafter 10 years, convergence after 5 years andconvergence after 3 years).Summary of resourceutilisation and cost dataThe authors collected resource use in their fieldstudy over 1 year and used these data to inform thecosts. The authors also calculated the costs due toproductivity losses.Summary of cost-effectivenessIn the analysis over 1 year the authors found thatfor high-risk patients EVAR was both less costlyand more effective than open surgical repair and assuch EVAR dominated open surgical repair.When a longer time horizon was specified EVARdoes result in more costs than open surgical repairunder all four assumptions regarding the survivalcurves. However, even when there is convergenceafter 3 years the incremental cost per QALY is stillonly $18,616 and as such EVAR still appears costeffective.CommentsGeneralThe results suggest that EVAR may be a costeffectiveuse of resources compared with opensurgical repair in high-risk patients.Internal validityThe use of non-randomised field study data raisesserious issues over the validity of these results.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48External validityThe study is conducted from a Canadianperspective and as such its applicability to the UKNHS is questionable. The study also takes accountof productivity losses, which is inappropriate froma UK NHS perspective and which raises furtherissues about the applicability of the results.Discussion of EVAR trial 1-typepopulation modelsThe studies considered in the previous sectionshave conflicting results, with some finding EVARto be a cost-effective use of resources 105,108,127and others finding it a non-cost-effective use ofresources. 106,107,126 The studies are consideredseparately in this section in light of the evidenceprovided by the other studies.Patel et al. 105 found that under their base-caseassumptions EVAR is a cost-effective alternative toopen repair in 70-year-old men with AAAs of 5 cmin diameter. This contrasts with UK studies (i.e.Epstein et al. 106 and Michaels et al. 107 ) which havefound that EVAR is not cost-effective comparedwith open repair in similar, if not identical,patient groups. Other authors (e.g. Prinssen etal. 126 ) have argued that the key reason for thecontradictory results produced by Patel et al. 105 isthat the combined and lasting mortality and severemorbidity rate used by the authors (1.1% for EVARversus 9.1% for open repair) was far too optimisticin favour of EVAR and that such a benefit was notshown in EVAR trial 1 or the DREAM trial. Asthe study is US based, and given the other issuesidentified, it does not appear possible to draw anyconclusions from it about the cost-effectiveness ofEVAR with regards to a UK NHS setting.Bosch et al. 108 found that, given typical thresholds,EVAR is likely to be considered cost-effectivecompared with open repair in 70-year-old menwith AAAs of between 5 and 6 cm in diameter.This contrasts with other more recent studies(e.g. Epstein et al. 106 and Michaels et al. 107 ) thathave found EVAR not to be a cost-effective use ofresources in similar patient groups. As the modelin Bosch et al. 108 has been parameterised based onnon-RCT data and the study is US based it doesnot appear reasonable to transfer its conclusions toa UK NHS setting.Michaels et al. 107 found that EVAR does not appearto be cost-effective in an EVAR trial 1-type patient(i.e. RC1 in their analysis). The high incrementalcost and low incremental effectiveness of EVARcompared with open surgery in patients who arefit for open surgery (RC1) is consistent with theresults of the other recent study. 106 However, thestudy was not able to make use of mid-term resultsfrom EVAR trial 1 as they were not available to theauthors at the time.Epstein et al. 106 found that EVAR was not a costeffectiveuse of resources in 74-year-old malepatients with AAAs of diameter ≥ 5.5 cm. Undertheir base-case assumptions they found that EVARwas dominated by open repair (i.e. it had highercosts but worse outcomes). This study was adaptedfor use in the economic model presented later inthis chapter (see York economic assessment).Prinssen et al. 126 found that, with a 1-year timehorizon, EVAR is dominated by open repair (it hashigher costs and lower effectiveness) in patientswith AAAs of diameter ≥ 5 cm. The approach takenby the authors of this study raises issues about thevalidity of the results produced. Most importantly,the short time horizon means that any post 1 yeardifferences between arms have not been captured.However, despite there being no extrapolation ofresults over the patients’ lifetimes the conclusionsappear to be consistent with those of Epstein etal. 106 and Michaels et al. 107 These three papersappear to be the most relevant published studiesfrom a UK perspective.The authors of the unpublished Medtronic study 127found that, under their base-case assumptions,EVAR is a cost-effective use of resources comparedwith open surgery in the EVAR trial 1 patientpopulation. This contradicts the results of bothMichaels et al. 107 and Epstein et al. 106 , who foundthat in the same population EVAR was not a costeffectiveuse of resources. The York economicassessment presents a decision model comparingEVAR and open repair that investigates the mainassumptions made by each of these authors inmore detail. Table 53 summarises the studies andprovides the base-case cost-effectiveness results.Cost-effectiveness studies focusingon the EVAR type 2 populationThis section considers economic evaluation studiesfocusing on a patient population which is similar tothat in EVAR trial 2 (i.e. patients considered unfitfor open repair).95© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 53 Summary of studies considering EVAR trial 1-type populationsStudy Summary Patient population QALYs Costs ICERMichaels2005 107 (RC1)Bosch 2002 108Patel 1999 105Markov model comparingEVAR with open repairMarkov model comparingEVAR with open repairMarkov model comparingEVAR with open repairEpstein2008 106 Markov model comparingEVAR with open repairPrinssen2007 126 Within-trial analysiscomparing EVAR withopen repairMedtronic2007 127 Markov model comparingEVAR with open repairCiC, commercial-in-confidence.Fit 70-year-old patientswith an AAA of 5.5 cmdiameter70-year-old men with anAAA of between 5 and6 cm in diameter70-year-old men with anAAA of 5 cm in diameterMale patients aged 74years with an AAA ofdiameter ≥ 5.5 cmFit patients with an AAA of≥ 5 cm in diameterPatients with an averageage of 70 years, 90% ofwhom are men, and withan AAA of at least 5.5 cmin diameter0.10 £11,449 £110,000 perQALY0.22 US$179 US$9905 perQALY0.42 US$9587 US$22,836per QALY–0.020 £3578 EVARdominated–0.01 €4968 EVARdominated(CiCinformationhas beenremoved)(CiCinformationhas beenremoved)£15,681 perQALY96Michaels et al. Cost-effectivenessof endovascular abdominalaortic aneurysm repair 107OverviewThis study evaluated the cost-effectiveness of EVARcompared with open repair in patients fit forsurgery (RC1) or with conservative management inthose unfit for surgery (RC2). The aim of the studywas to determine an optimal strategy for the use ofEVAR based on the best available evidence at thetime. The study was published before the results ofthe EVAR trial 2 were available.Effectiveness and resource use data were based onrecent RCTs (EVAR and DREAM) as well as on asystematic review of the literature. The authorsdeveloped a Markov model and used it to considertwo separate ‘reference cases’, one of which, RC1,was discussed in the previous section. In thissection we will consider their modelling of 80-yearoldpatients with an AAA of 6.5 cm diameterwho were considered unfit for open surgery andfor whom the choice of treatment was betweenEVAR and conservative management (RC2). Theprimary outcome measure for the cost-effectivenessanalysis was the incremental cost per QALY gained.The authors used a 10-year time horizon. Theevaluation was undertaken from the perspective ofthe NHS.The model for RC2 is similar to that of RC1(Figure 65) with the surgery arm being replacedby a conservative management arm. Conservativemanagement in this model excludes the option forelective surgery.Summary of effectiveness dataShort-term operative mortality probabilitieswere taken from the EVAR 42 and DREAM 40 trials.However, it should be noted that these trialswere conducted in patient populations whowere considered fit for open repair and thusthe mortality probability of EVAR found mightnot be applicable to the less healthy patientpopulation considered here. The probabilities ofreintervention and complications were derivedfrom a previously conducted systematic review.General mortality was taken from standardisedmortality tables for England and Wales. Aneurysmrelatedmortality was calculated from a previousmodelling study.Rupture rates for conservative management werebased on three published studies 130–132 and are afunction of aneurysm size. Expansion rates werealso taken from other studies. 132–140 It shouldbe noted that these studies are dated (all werepublished before 1992) and may not accurately

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48reflect the current natural history of untreatedaneurysm.Utility estimates were based on published figuresderived from the EQ-5D tariff values for men aged65–74 years. To account for the lower HRQoLinitially following surgery, a reduction in keepingwith that seen after major surgery was appliedfor the first 2 weeks after EVAR. QALYs werediscounted at a rate of 3.5% per annum.The key effectiveness parameters for the model arereported in Table 54.Summary of resourceutilisation and cost dataMost costs were based on NHS reference costsfor 2003–4 123 with the mean cost being thepoint estimate. For the probabilistic sensitivityanalysis a normal distribution was assumed withstandard deviation based on the assumption that50% of observations were within the publishedinterquartile range. The procedure cost of EVARwas assumed to be the average national NHSreference cost for open surgery plus an additionalincremental cost of EVAR estimated from datacollected at the Sheffield Teaching Hospital NHSTrust. Follow-up costs for EVAR were based on NHSreference costs with the assumption that on averagean EVAR patient will have two outpatient visitsand two CT scans per year. It is not clear from thepublished paper if patients in the no surgery armreceived continuing surveillance. The average costof a reintervention in the EVAR arm again usedNHS reference costs but was based on the case mixof reinterventions as recorded in the EUROSTARregistry. 124 All costs have been discounted at a rateof 3.5% per annum. Table 55 summarises the keyresource cost parameters from the study.Summary of cost-effectivenessRC2 reference caseThe base-case results for RC2 showed that EVARresulted in increased QALYs (1.64 QALYs)compared with conservative management butalso extra costs (£14,077), resulting in an ICER of£8579 per QALY.A variety of sensitivity analyses was also undertakenon the RC2 reference case. The ICERs for the RC2group ranged from £5215 per QALY (when initialincremental cost of EVAR was reduced to £0) to£19,971 per QALY (when the time horizon wasreduced to 5 years).The authors also undertook a probabilisticsensitivity analysis. All of the simulations generatedan ICER of less than £30,000 per QALY (i.e. theprobability of the ICER being less than £30,000per QALY was 1). Table 56 presents the ICERs forthe RC2 base case and for some of the sensitivityanalyses conducted.CommentsGeneralMichaels et al. 107 found that EVAR may be a costeffectiveintervention in patients who are unfit foropen surgery. With a 10-year time horizon theyfound that, compared with medical management,EVAR resulted in more QALYs at a higher cost,giving an ICER of £8579 per QALY.TABLE 54 Key effectiveness parameters from Michaels et al. 107Key parameters Value SourceMortality of primary EVAR for first month post surgery (%) 1.85 EVAR trial 1 42 and DREAM 40Probability of conversion of EVAR to open repair (%) 1.9 Drury et al. 121Utility for living patient following treatment 0.8 Health Survey for England 1996 122TABLE 55 Key resource cost parameters from Michaels et al. 107Key resources Cost SourceCost of EVAR repair £8769 Sheffield Teaching Hospital NHS TrustEVAR follow-up cost per month £41.50 NHS reference costs 123Reintervention £4790 NHS reference costs 123 and EUROSTAR 12497© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceTABLE 56 Key cost-effectiveness results from Michaels et al. (RC2) 107ScenarioResultBase-case ICER (RC2)£8579 per QALYDiscounted mean incremental QALYs generated by EVAR compared with no surgery (RC2) 1.64Discounted mean incremental cost of EVAR compared with no surgery (RC2) £14,077Sensitivity analyses/alternative assumptionsEVAR procedure costs the same as average cost of open repair5-year time horizon£5215 per QALY£19,971 per QALY98Internal validityThis study was conducted before the EVAR trial2 long-term results were published and has thusrelied on other sources to parameterise the model.Some of the parameters have been derived fromnon-randomised sources and are thus open to bias.The use of the EVAR trial 1 operative mortality ratealso appears inappropriate given the differencesbetween the patient group considered in this study(one that is unfit for open surgery) and the EVARtrial 1 population (all of whom were considered fitfor open surgery).External validityThe study is UK based and has been conductedfrom the perspective of the NHS. However,estimates of aneurysm growth rates and rupturerates in untreated patients from the literature maynot reflect rates expected in patients anatomicallysuitable for EVAR.EVAR trial participants – Endovascularaneurysm repair and outcome inpatients unfit for open repair ofabdominal aortic aneurysm (EVAR trial2): randomised controlled trial 46OverviewEVAR trial 2 investigated whether EVAR improvedsurvival compared with no intervention in patientswho were considered unfit for open repair.Although it was not explicitly a cost-effectivenessstudy, we review it in this section because the studyreported life expectancy and costs, and there havebeen no other cost-effectiveness analyses publishedin the light of the results of this trial. The meanage of patients in the EVAR arm was slightly higherthan in the no intervention arm (76.8 years versus76.0 years, respectively). The mean AAA diameterwas also marginally larger in the EVAR arm thanin the no intervention arm (6.4 cm versus 6.3 cm,respectively).In the trial patients were followed up over 4 yearsand data on mortality, HRQoL (measured bythe EQ-5D and the SF-36) and resource use werecollected over this period.Summary of effectiveness dataThe EVAR trial 2 found that the 30-day operativemortality rate for the EVAR group was 9%. The nointervention group was found to have a rupturerate of 9.0 per 100 person-years. By the end of the4 years, overall mortality was around 64% and thisdid not significantly differ between the two trialarms. The trial also found no significant differencein aneurysm-related mortality between the two trialarms.HRQoL data was collected from the EVAR armpatients at 1, 3 and 12 months after the operation,whereas for the no intervention arm it was collectedfrom the patients at 2, 4 and 13 months afterrandomisation (this was based on the assumptionthat it would take 1 month following randomisationfor the EVAR procedure to be performed). No clearand consistent differences in HRQoL between thetwo trial arms were found.Summary of resourceutilisation and cost dataResource use and cost estimations were calculatedusing the same methods as those used in EVARtrial 1 (e.g. data on resource use were collectedusing case report forms, which were thenmultiplied by unit costs to calculate total costs).Resources considered included, among others,initial procedure resource use, hospital stay,secondary AAA procedures, outpatient visits andsurveillance using CT.The study found that the EVAR arm hadconsiderably greater mean hospital costs perpatient than the no intervention arm (£13,632versus £4983 respectively).

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Summary of cost-effectivenessThe study found that EVAR did not improveHRQoL over the follow-up period, had a high30-day operative mortality rate, had no 4-yearsurvival benefit and had considerably higher coststhan in the no intervention arm. Therefore, inthe patient group considered (patients of around66 years of age with an AAA of approximately6.5 cm in diameter) it appeared that EVAR may bedominated by the no intervention arm (i.e. EVARhas higher costs and worse outcomes).CommentsGeneralEVAR trial 2 investigated whether EVAR improvedsurvival compared with no intervention in patientswho were considered unfit for open repair. Thisstudy found that EVAR led to no improvement inoutcomes but had a higher cost.Internal and external validityIn Chapter 3 several issues that complicate theanalysis of the EVAR trial 2 were discussed. Theseinclude the long delay between randomisation andprocedure and the fact that a number of individualsin the no intervention arm received EVAR or openrepair. This raises issues over the validity of thestudy in terms of whether it accurately captures thecosts and benefits of the two strategies (EVAR or nointervention) it aimed to evaluate.Summary of studies consideringEVAR trial 2-type populationsTable 57 summarises the results of the two studiesconsidering an EVAR trial 2-type population.Michaels et al. 107 found EVAR to be a costeffectiveuse of resources compared with medicalmanagement in AAA patients who are consideredunfit for open surgery. The results produced forthe RC2 group, however, do not agree with theresults from EVAR trial 2, 46 which found thatthe EVAR arm was dominated by the medicalmanagement/no intervention arm (i.e. EVAR wasmore costly and with similar survival at 4 years).However, as discussed above there were issues withthe EVAR trial 2 which may mean that its resultsdo not accurately reflect the costs and benefitsof the intended strategies. An economic modelpresented later in this chapter aims to add to theevidence from the RCT by bringing together theavailable evidence on costs and outcomes in treatedpatients with the limited data on natural historyin untreated patients, to compare the strategies ofsurgery, no surgery or watchful waiting (see Modelcomparing immediate elective surgery, watchfulwaiting and no intervention).York economic assessmentIntroductionThe York economic assessment is divided into twocomplementary parts. The first part will comparethe cost-effectiveness of EVAR versus open repairin patients with large aneurysms. This analysisassumes that the decision to operate has alreadybeen taken. The second part estimates the costeffectivenessof policies on when, as well as how, theaneurysm repair should be carried out. As well asEVAR and open repair we consider no surgery andwatchful waiting as alternative policies.We consider that the population of patients withlarge aneurysms is clinically heterogeneous, whichmay mean that cost-effectiveness differs betweenpatient groups. We show how the results might beaffected by three key patient characteristics: age,fitness (risk of operative mortality) and aneurysmTABLE 57 Summary of studies for EVAR trial 2-type populationsStudy Summary Patient populationMichaels2005 107 (RC2)Markov modelcomparing EVARwith medicalmanagementEVAR trial Within-trialparticipants analysis2005 46 comparingEVAR with nointervention80-year-old patientswith an AAA of 6.5 cmdiameter who wereconsidered unfit foropen surgery76-year-old patientswith a meanAAA diameter ofapproximately 6.3 cmwho are consideredunfit for open repairIncremental QALYs,EVARIncrementalcosts, EVARICER1.64 £14,077 £8579 perQALYNot stated £8649 EVARdominated byno interventionarm99© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidencesize. Each variable affects the parameters of themodel in a distinct way. Chapter 3 found age to bea risk factor for operative mortality in most studies,as well as for long-term survival, independentof aneurysm diameter and other factors. Fitnessin this model represents pre-existing conditionsexamined in Chapter 3, such as cardiac, pulmonaryor renal insufficiency, which might be predictiveof operative mortality. 141 However, the largenumber of combinations of potential risk factorsand levels would make the presentation of resultscumbersome if stratified in this way. It is moreconvenient to express fitness according to a singlescale. In this analysis we define four levels ofoperative fitness:• good fitness, or no pre-existing conditionsaffecting operative mortality• moderate fitness, with twice the odds ofoperative mortality compared with a personof the same age and aneurysm size with goodfitness• poor fitness, with four times the odds ofoperative mortality compared with a personof the same age and aneurysm size with goodfitness• very poor fitness, with eight times the odds ofoperative mortality compared with a personof the same age and aneurysm size with goodfitness.From a clinical perspective these relative(un)fitness scores could in principle arise fromany combination of factors. For example, Chapter3 showed the evidence on the use of the GAS topredict early and late mortality in EVAR and openrepair. 59 Unfortunately, no scoring system hasachieved widespread acceptance. 142 Furthermore,in practice, clinicians are skilled at subjectivelyassessing ‘fitness’ and Chapter 3 showed that theseassessments are predictive of both short- and longtermmortality after surgery. 23,65 Therefore, for thisanalysis we have used a general ‘fitness’ score asdefined above.We believe it is important that the model reflectsclinical heterogeneity for three reasons. First, ifcost-effectiveness differs between patient groupsthen it may be efficient to limit the use of EVARto patients in whom it is cost-effective. Second,even if there are practical or ethical reasons thatmake it difficult to limit EVAR to particular patientgroups, the decision model should neverthelessincorporate heterogeneity. Inputs to the modelsuch as operative mortality and late mortality arecorrelated as they depend on common clinical riskfactors. If the case mix of the target populationdiffers from that of the trial population thenthese inputs to the model must be adjusted forthe appropriate case mix in a consistent manner.Third, if results depend on clinical factors, furtherresearch should be directed towards understandingand if possible mitigating those risks.The following section describes the methods andresults of the York model for the comparisonof EVAR with open repair. This is followed by asection describing the methods and results of amodel for the comparison of surgery with watchfulwaiting. The chapter concludes with a discussion.Comparison of EVARand open repairModel comparing EVAR and open repairin patients with an AAA of at least 5.5 cmand considered fit for open repairOverviewThe model compares a strategy of open repair withthat of EVAR for patients with a diagnosed AAA ofat least 5.5 cm in diameter and considered fit foropen repair. The perspective of the model is thatof the UK NHS. The measure of health benefit isexpected QALYs over the patient’s lifetime. Theprice year is 2007 and all costs are measured in UKpounds. Costs and health benefits in future yearswere discounted at a rate of 3.5% per year. 15 Themodel is closely based on a previously publishedmodel undertaken by some of the assessmentteam . 106 The main difference is that this modelextends the analysis for patients of different ages,fitness levels and aneurysm sizes at the time ofthe decision to undertake surgery. 143 The basecasemodel assumed that these factors influencedbaseline risks but that the effect of treatment onoperative mortality (OR of EVAR versus openrepair) was constant for all patient groups.The analysis seeks to provide estimates of thecost-effectiveness of management options forall patients in the relevant AAA populations.However, it should be emphasised that mostRCT and registry data on EVAR relate to men(see Chapter 3). The cost-effectiveness of EVARversus open repair in women is explored in asecondary analysis, given the limited data available.Furthermore, untreated rupture rates may differbetween men and women and the implications ofthis are discussed in the model comparing surgerywith watchful waiting.100

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Model structureThe model starts after the decision to operate hasbeen made. The model structure is shown in Figure69. Patients enter the model and have a primaryaneurysm repair procedure (i.e. either EVAR oropen repair). Following this, patients may die,convert to open repair or survive the procedure.Survivors pass into a Markov cohort model toestimate lifetime costs and QALYs. It has beenassumed that patients who convert from EVAR toopen repair during the primary admission havethe same long-term prognosis as patients initiallyundergoing open repair. Unlike the model shownin Epstein et al., 106 this model does not estimatethe incidence of cardiovascular complicationssuch as stroke and myocardial infarction, as theclinical review (Chapter 3) found no evidence thatthe incidence of these events differed betweentreatments in the short or long term.Parameter estimationOperative mortality: equation 1Estimation of odds ratio of the treatment effect Thetreatment effect for operative mortality wasobtained from the synthesis of the RCTs 41,43,44reported in Chapter 3. The pooled OR for 30-daymortality from these trials is 0.35 (95% CI 0.19to 0.63). The base-case analysis considers the ORfor treatment effect to be constant (proportional)for all patient groups. This assumption has beeninvestigated in two studies 23,96 (see Chapter 3).Brown et al. 23 examined the impact of varyingfitness level (assessed by a modified version of theCPI fitness score) on data from the EVAR trial 1and found no significant interaction (p = 0.28)when fitness was considered a continuous variable.Schermerhorn et al. 96 compared operativemortality in a non-randomised cohort of Medicarebeneficiaries, adjusting by a propensity score to tryto control for selection bias. They found that theOR for treatment effect was similar across all agegroups, although the OR tended to be greatest inthe youngest (and therefore the fittest) patients:the OR for EVAR versus open repair for all ageswas 0.25 (95% CI 0.22 to 0.28), and for ages 67–69years was 0.16 (95% CI 0.13 to 0.20).Estimation of the baseline risk of operative mortality Theprobability of operative mortality after EVARwas estimated for different patient groups. Thisrepresents the baseline risk of death at 30 days. Alogistic regression was constructed using individualpatient data from patients enrolled in EUROSTARbetween 1994 and 2006. 54 EUROSTAR data wereused because, as described in Chapter 3, these arethe most relevant to current clinical practice forEVAR. The explanatory variables were selectedfrom those assessed in Chapter 3: age (continuous),gender, smoking status, ASA status III or IV, preexistingconditions, renal function, fitness for openprocedure, aneurysm size (in 0.5-cm increments),aortic neck and aneurysm angle, aortic necklength and graft configuration and device type. Toreflect improved outcomes arising from changesin patient selection, devices and procedures, avariable was included to indicate whether thepatient was enrolled after 31 December 1999. Theresults of the regression are shown in Table 58 forConversion toopen repairPrimaryadmissionNon-fatalsecondaryre-admissionEquation 4Equation 2:Other causedeathNo eventEquation 3:Late AAAdeathEquation 1:30-dayoperativedeathDeathFIGURE 69 Model structure, once a decision to treat has been made.101© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidencethe statistically significant variables. The predictedprobabilities of operative mortality after EVARand after open repair calculated in the base-casemodel are shown in Table 59 for patients of good,moderate and poor fitness at various ages andaneurysm sizes. Fitness is defined in a generalway as described in the introduction to the Yorkassessment model, such that a patient with goodfitness of a given age and aneurysm size is assumedto have none of the risk factors in Table 58, apatient with moderate fitness is assumed to havetwice the odds of operative mortality of a patientwith good fitness and a patient with poor fitness isassumed to have four times the odds of operativemortality of a patient with good fitness.Long-term modelChapter 3 found that the early advantage of EVARin terms of operative mortality diminished overthe medium term, with no statistically significantdifference in overall survival after about 2 yearsbased on the results of the EVAR trial 1 43 andDREAM trial. 41 As discussed in Chapter 3 thecause of this erosion of the early survival advantageafter EVAR is unclear. One factor may be a greaterrisk of rupture or aneurysm-related death afterEVAR than after open repair. It may also be aconsequence of the natural variability in the fitnessof the population with large AAAs. It may be thatopen surgery precipitates operative mortality inpatients who were already at high risk from otherconditions and who would have died of othercauses in the medium term. It is also possible thatit is simply a chance finding in both trials.To reflect this uncertainty in the reasons for theerosion of the early survival advantage afterEVAR, the model was constructed in such a waythat different scenarios about patient prognosisfollowing repair of the aneurysm could beexplored, based on the available evidence. Theoverall late mortality rate, h(t), at time t can bewritten as the sum of two competing risks: deathfrom non-aneurysm-related causes (h Other) (equation2 in Figure 69) and late death from aneurysmrelatedcauses (h AAA) (equation 3 in Figure 69):h(t) = h Other(t) + h AAA(t)Each of these separate risks is discussed in thefollowing sections.Estimation of the rate of non-aneurysm-relateddeaths more than 30 days after aneurysm repair:equation 2The rate of non-aneurysm-related deaths in themodel after more than 30 days, h Other(t), was in turnconstructed from the product of three components:the rate of non-aneurysm-related deaths in thegeneral population, h 0(t), multiplied by the relativerisk in patients with a large AAA after aneurysmrepair, HR LargeAneurysm, multiplied by the relativerisk after an EVAR procedure compared with openrepair, HR EVAR(t). Formally, this can be expressed as:h Other(t) = h 0(t) × HR LargeAneurysm× HR EVAR(t)These three components of non-aneurysm-relateddeath after surgery in the model are illustrated inFigure 70. Mortality rates in the general population(h 0) were estimated from life tables, 144 adjusting foraneurysm mortality. 145 The parameter HR LargeAneurysmcan be thought of as representing the generalprognosis for survival free from non-aneurysm-TABLE 58 Results of logistic regression of deaths within 30 days of EVAR, from the EUROSTAR data 1994–2006 (equation 1 inFigure 69)Patients included in the model 9667Deaths 230Log likelihood –992102Coefficient SE (coefficient) Odds ratioPer year of age over or under 74 years 0.07 0.01 1.074Per cm AAA over or under 5.5 cm 0.30 0.05 1.347Older device 0.43 0.16 1.537Unfit for open surgery 0.63 0.14 1.879Renal condition 0.68 0.14 1.974ASA III or IV 0.70 0.17 2.023Constant –4.89 0.16

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 59 Predicted probabilities of operative mortality after EVAR and open repair in the base-case model in patients of good,moderate and poor fitness, for different ages and aneurysm diametersEVARAge (years)Open repairAge (years)Aneurysm 5.5 cm70 75 80 70 75 80Fitness Good 0.006 0.008 0.011 0.015 0.021 0.030Aneurysm 6.5 cmModerate 0.011 0.016 0.022 0.030 0.042 0.060Poor 0.022 0.031 0.044 0.060 0.085 0.122Fitness Good 0.008 0.011 0.015 0.020 0.029 0.041Moderate 0.015 0.021 0.030 0.040 0.057 0.081Poor 0.030 0.042 0.059 0.080 0.115 0.164Operative mortality after EVAR is estimated from the logistic regression shown in Table 58, and that after open repairassuming that the pooled odds ratio estimated in Chapter 3 applies to all patient groups.related death after aneurysm repair for a personof that fitness and aneurysm size relative to thegeneral population of that age. The review of riskfactors in Chapter 3 found that aneurysm size atthe time of the procedure was predictive of theprobability of long-term survival after EVAR. Thisis thought to be primarily cardiovascular risk.Brady et al. 146 found a strong association betweenaneurysm diameter and the risk of non-aneurysmrelatedcardiovascular mortality after aneurysmrepair in the UK Small Aneurysm Trial and Study:the relative risk of cardiovascular death increasedby 31% for each standard deviation increase inaneurysm diameter on a log scale (about 0.8 cmon the natural scale), after adjusting for other riskfactors. We estimated the relationship between risk0.40Rates of non-aneurysm mortality per year0.350.300.250.200.150.10Predicted non-aneurysmmortality rate after EVARPredicted non-aneurysmmortality rate after openrepairHazard ratio for non-aneurysm mortality afterEVAR compared with open repair HR EVARHazard ratio for non-aneurysm mortality for patients afteraneurysm repair compared with general populationHRlarge aneurysm0.05Non-aneurysm mortality rate in the generalpopulation0.0075 76 77 78 79 80 81 82 83 84 85AgeFIGURE 70 Rates of mortality from non-aneurysm-related causes after EVAR and open repair used in the base-case model for a patientaged 75 years with an AAA of 5.5 cm and of poor fitness at baseline.103© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidencefactors and non-aneurysm-related deaths using aCox survival regression based on the EUROSTARdata set, censoring on AAA deaths. The results ofthis analysis are shown in Table 60.In the decision model, patients with small (< 5 cm)aneurysms and no other risk factors were assumedto have the same risk of non-aneurysm-relatedmortality as the general population of the sameage and gender. As shown by the HRs in Table 60,a patient with a large aneurysm at surgery (5.5 cm)would expect a rate of non-aneurysm-related death34% greater than that in the general population ofthe same age; this value would be 76% greater ifthe aneurysm were ≥ 6.5 cm at surgery.The clinical review in Chapter 3 found that therewere several factors, such as renal insufficiency andASA class, that were strongly associated with bothoperative death and long-term survival. The riskmodelling shown in Tables 58 and 60 confirms thesefindings and furthermore finds that these factorsare associated with late non-aneurysm-relateddeaths. This correlation between factors predictiveof operative death and late non-aneurysm-relatedmortality lends support to the hypothesis that openrepair is precipitating deaths in the most riskypatients. As described earlier in this chapter (seeIntroduction), here we aimed to define fitness in ageneral way, rather than specifying results for everypossible risk factor and combination of factors.However, we need to include the correlationbetween early and late mortality in the model inorder to estimate life expectancy for a patient ofa given operative fitness. The best way to estimatethis correlation would be to calculate the risk oflate non-aneurysm-related mortality associated witheach level of a validated and generally acceptedoperative risk scoring system. As we do not havesuch a risk scoring system, we illustrate the modelfor groups with different levels of operativefitness as follows. We consider patients with renalinsufficiency to represent a moderate fitness group,with about twice the odds of operative mortality(OR 1.97, Table 58) and a 40% greater risk of latenon-aneurysm-related mortality (HR 1.39, Table60), and patients with both renal insufficiency andASA class III or IV to represent a group with poorfitness, with almost four times the odds of operativemortality (1.97 × 2.02 = 3.99, Table 58) and almostdouble the risk of late non-aneurysm-relatedmortality (1.39 × 1.40 = 1.95, Table 60). Furtherwork will be needed to confirm these estimates ofthe correlation between early and late mortality indifferent populations using validated risk scoringsystems.Rate of convergence of survival curves for nonaneurysm-relatedmortality after EVAR and open repair(HR EVAR) Given that the EVAR trial 1 and DREAMtrial found that the early survival advantageafter EVAR was not maintained over the mediumterm (Chapter 3) it is necessary to estimate therate of convergence of the survival curves afterthe primary admission (parameter HR EVAR, seeFigure 70). A large US matched-cohort study 96 (seeChapter 3) found that both the initial differencein operative mortality of EVAR compared withTABLE 60 Results of Cox survival analysis of the rate of non-aneurysm-related deaths more than 30 days following aneurysm repair,from the EUROSTAR data 1994–2006Coefficient SE (coefficient) Hazard ratio aPer year of age over 74 years 0.043 0.004 –Unfit for open surgery 0.396 0.076 1.49AAA 5.1–5.4 cm 0.185 0.112 1.20AAA 5.5–5.9 cm 0.290 0.113 1.34AAA 6–6.4 cm 0.429 0.116 1.54AAA 6.5+ cm 0.565 0.108 1.76Older generation 0.141 0.070 1.15Pulmonary condition 0.250 0.067 1.28ASA III or IV 0.334 0.070 1.40Renal condition 0.332 0.076 1.39104a The hazard ratio is the exponential of the coefficient. The hazard ratio for age is not shown because this is included inthe Cox analysis only as an adjustment factor. The model calculates relative risks of non-aneurysm-related mortality forpatients with relevant risk factors compared with mortality rates in the general population of a given age.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48open repair and the time taken for the survivalcurves to meet strongly depended on age. Youngerpatients (67–74 years) had an absolute differencein operative mortality of less than 2.5% but theproportion surviving at 18 months was the sameafter EVAR and open repair. On the other hand,85-year-olds had an absolute reduction of 8.5% inoperative mortality and the difference in survivalwas maintained between the groups until 4 years(Figure 71). These results suggest that, even thoughthe process causing the survival curves to convergemight be unknown, the phenomenon is observed inall patient fitness groups. Furthermore, the benefitof EVAR is prolonged in those patient groups withthe greatest difference in operative mortality.The EVAR trial 1 divided the follow-up intothe first 6 months after randomisation and theperiod from 6 months (to allow for delays betweenrandomisation and surgery) and calculated allcausemortality HRs for the two periods to be 0.55(95% CI 0.33 to 0.93) and 1.10 (95% CI 0.80 to1.52) respectively (see Chapter 3). However, theHR for 6 months onwards is not directly useable inthe model as we need the HR for non-aneurysmrelateddeaths occurring more than 30 days afterthe procedure. In the intention to treat analysisthe EVAR trial 1 found 81 deaths (seven aneurysmrelated) occurring more than 30 days after theprocedure in patients randomised to EVAR and 71deaths (two aneurysm related) occurring more than30 days after the procedure in those randomisedto open repair. 43 In the base-case model we assumean HR of late non-aneurysm-related death of 1.072(74 versus 69 deaths) as an estimate of HR EVAR(t),given that the number of patients and mean lengthof follow-up in the groups were similar. This isassumed to apply to the EVAR group until the non-(a)1.00.9All agesEndovascular repair(b)1.00.9Open repair67–74 yearsEndovascular repairProbability of survival0.80.70.60.5Open repairProbability of survival0.80.70.60.50.40.00 6 12 18 24 30 36 42 48 54 60Months0.40.00 6 12 18 24 30 36 42 48 54 60Months(c)1.075–84 years(d)1.0

Assessment of cost-effectiveness evidenceaneurysm-related survival curves converge, andfor non-aneurysm-related deaths to be the samein both arms thereafter [HR EVAR(t) = 1]. Sensitivityanalysis explored other scenarios.Estimation of the rate of late aneurysm-related death:equation 3Hazard ratio for treatment effect for late aneurysmrelateddeaths Chapter 3 found that the differencein aneurysm-related death between EVAR andopen repair is maintained up to 4 years. Even if therate of late aneurysm death is low, it is importantto include it in the model if it is thought thatthere might be a persistent difference between therates after EVAR and open repair. The HR (EVARrelative to open repair) for aneurysm-relatedmortality 6 months or more after randomisationestimated by the EVAR trial 1 was 1.15 (95% CI0.39 to 3.41), 43 with a wide confidence intervalbecause of the few deaths included (see Chapter3). However, this HR would seem to underestimatethe difference in observed aneurysm-related deathsoccurring more than 30 days after the primaryprocedure (seven after EVAR versus two after openrepair in about 1250 patient-years of follow-up ineach arm), perhaps because some of the deathsoccurred in the first 6 months. For the base-casevalue in the model we estimated the HR (EVARrelative to open repair) from EVAR trial 1 for lateaneurysm-related deaths occurring more than 30days after the primary procedure, censoring onother causes of death. This was estimated to be2.46 (95% CI 0.48 to 12.7). 106 However, this is nota randomised comparison because of differentlengths of time from randomisation to surgeryin the two arms. On the basis of clinical opinionwe used a HR of 1.5 for the base case. Sensitivityanalysis explored other estimates.Baseline rate of late aneurysm-related deaths occurringmore than 30 days after EVAR Chapter 3 foundthat baseline aneurysm size was associated withaneurysm-related death after EVAR in most studies.We estimated the baseline rate of aneurysm-relateddeath after EVAR occurring after 30 days usingthe EUROSTAR data set for patients enrolledbetween January 1994 and November 2006,censoring on other causes of deaths. 54 Table 61shows the data stratified by the date of enrolmentand AAA diameter at enrolment. The mean rateof late aneurysm-related death for recent patientswas 0.4% per year in patients with large AAA (5.5–6.4 cm) and 1.2% per year in patients with verylarge AAA (> 6.5 cm). These rates are lower thanthose found in an earlier published analysis of theEUROSTAR data, 82 but confirm the earlier findingthat rates of late aneurysm-related mortality afterEVAR are strongly associated with aneurysm sizeat the time of the procedure (see Chapter 3). Thehigher rate in earlier enrolments might indicateimprovement in devices and procedures but couldalso arise because patients were followed up for alonger period, with more time for the aneurysmto expand, or because of more cautious patientselection.It is uncertain whether, for any given patient, therisk of late aneurysm-related death is constant,increasing or decreasing with time from surgery.Peppelenbosch et al. 82 estimated that the risk oflate aneurysm-related death tended to increasewith time from surgery, using EUROSTAR data forpatients enrolled from 1996 to 2002. For patientswith large aneurysm (5.5–6.5 cm) the rate of lateaneurysm-related death was 0.3% in the first 3years rising to 2.1% after 4 years. For patients withvery large aneurysm (> 6.5 cm) the rate was 1% inthe first 3 years rising to 8% in the fourth year.This apparent increase in the risk of death withtime from EVAR may be confounded by evolutionof devices and surgical technique, as those patientswith the longest follow-up underwent EVAR withthe oldest devices. We tried to adjust for this byTABLE 61 Late aneurysm-related deaths, excluding operative mortality, in patients undergoing EVAR. EUROSTAR data stratified byenrolment date and baseline AAA diameter106Enrolmentdate AAA size nBefore 1January 2000After 1 January2000Deaths byNovember 2006Patient-yearsat riskMean follow-up(years) per patientMean rateper year< 5.5 cm 1200 24 4753 3.96 0.5%5.5–6.4 cm 786 34 2977 3.79 1.1%≥ 6.5 cm 435 30 1410 3.24 2.1%< 5.5 cm 2296 10 4296 1.87 0.2%5.5–6.4 cm 2211 16 4116 1.86 0.4%≥ 6.5 cm 1340 28 2311 1.73 1.2%

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48estimating parametric survival models, including avariable representing the year that the device wasfitted. Table 62 shows the results of the parametricsurvival regression using the EUROSTAR data(1994–2006) for a log-normal, a Weibull and anexponential (constant hazard) distribution. Figure72 shows the rate of aneurysm-related death overtime predicted by each regression model (forpatients aged 74 years with an AAA of 5.5 cm). TheWeibull and log-normal models estimate similarrates of aneurysm-related death during the first5 years, the hazard increasing over time for thesepatients to a maximum of about 0.4%. The Weibullmodel then predicts that the hazard continuesto gradually increase over time, whereas the lognormalmodel predicts that the rate after 5 yearsthen gradually decreases over time. The averagerate (exponential model) for this patient group was0.33%.Hence, there is considerable uncertainty aboutthe relationship between late aneurysm-relateddeath and time from surgery. The base-case modelassumed that the rate of late aneurysm-relateddeath was constant from 1 month after surgery(exponential survival model). Sensitivity analysesexplored alternative scenarios. An increasing ratemight correspond with a belief that the aneurysmcontinues to expand after EVAR, whereas adecreasing rate might correspond with a beliefthat patients at risk will be successfully identifiedby long-term surveillance and receive appropriatetreatment.Illustration of differences in operative, aneurysmrelatedand non-aneurysm-related causes of deathbetween EVAR and open repair in the base-case modelFigure 73 illustrates how predicted death ratesfor each cause differ in the base-case modelbetween EVAR and open repair. The figure showsthe differences in the cumulative rates of deathbetween the treatments (in patients at risk upto time t) for all-cause deaths, AAA deaths andnon-AAA death. The initial difference in favourof EVAR is due to a benefit in early operativemortality. There is a continuing difference inlate aneurysm-related mortality between thetreatments. There is also a difference in late nonaneurysm-relateddeaths because of there beinga greater proportion of patients with poor fitnessamong survivors of EVAR than among survivors ofopen repair. This higher rate of mortality persistsuntil the survival curves for late non-aneurysmrelateddeath converge, in this case at about 4years. Although there is a persisting difference inaneurysm-related deaths after the survival curvesmeet, this has only a small effect on all-causemortality because of the relatively high competingrisk of deaths from other causes (Figure 74).TABLE 62 Results of log-normal, Weibull and exponential survival models of the rate of aneurysm-related deaths occurring more than30 days following aneurysm repair with EVAR, from the EUROSTAR data (equation 3 in Figure 69)Number of observations 8182Number of deaths 142Patient-months (patientyears)228,471(19,039)Log-normal model Weibull model Exponential model (base case)Coefficient SE Coefficient SE Coefficient SEPer year of age over 74 years –0.04 0.01 0.04 0.01 0.04 0.01AAA size 5.5–5.9 cm –0.48 0.25 0.52 0.26 0.52 0.26AAA size 6–6.4 cm –0.64 0.26 0.69 0.27 0.68 0.27AAA size 6.5+ cm –1.35 0.23 1.33 0.22 1.32 0.22Older generation –0.85 0.20 0.82 0.18 0.89 0.18Unfit for open repair –0.68 0.20 0.64 0.20 0.62 0.19Intercept 9.16 0.46 –9.00 0.39 –8.53 0.22Log sigma coefficient 0.81 0.07Log shape coefficient 0.12 0.08Log likelihood –731 –728 –729107© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidence0.006Rate/year of death after first 30 days0.0050.0040.0030.0020.001Mean AAA deaths, EUROSTAR WeibullMean AAA deaths, EUROSTAR log-normalMean AAA deaths, EUROSTAR exponentialExtrapolated after 6 years00.0 2.5 5.0 7.5 10.0 12.5 15.0YearsFIGURE 72 Predicted rates of aneurysm-related death occurring more than 30 days following aneurysm repair with EVAR for a patientaged 74 years, with an aneurysm diameter 5.5–5.9 cm, with a recent EVAR device and fit for open surgery. Estimated from EUROSTARdata using an exponential model, a Weibull model and a log-normal model. Dashed lines indicate extrapolation beyond the maximum of6 years of follow-up between 2000 and 2006.Rate of late readmission for complications:equation 4In the model patients are at risk of readmissionfor a secondary AAA procedure. We estimatereadmissions rather than late complicationsbecause for the purpose of the model we areprimarily interested in this outcome to predictthe use of health-care resources. The rate ofreadmission to hospital after discharge from theprimary admission was estimated from the EVARtrial 1 data using a Weibull model with deaths ascensoring variables. 106 The estimated coefficientsof the Weibull model are shown in Table 63. Asin Chapter 3 this regression did not find ageand pre-existing conditions to be associated withreadmissions, but, unlike Chapter 3, it also did0.08Difference in cumulative deaths for nonaneurysmcauses (EVAR less open)Difference in cumulative hazard of death by year t(EVAR less open)0.060.040.020–0.02–0.04–0.06–0.08Difference in cumulative deaths forall causes (sum of aneurysm causesand non-aneursym causes)2 4 6 8 10 12 14Difference in cumulative deaths foraneurysm causes (EVAR less open)Years(t)Initial benefit inoperativemortality isoffset by latenon-aneurysm108FIGURE 73 Illustration of the difference between the treatments in the cumulative rates of death (from aneurysm-related and nonaneurysm-relatedcauses) estimated in the base-case decision model for a patient aged 75 years with a large AAA (6.5 cm) and poorfitness.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 481.0Survival free of aneurysm-related mortality, EVAR0.9Survival0.80.70.60.50.40.30.20.1Overall survival,open repairSurvival free of aneurysm-related mortality, open repairOverall survival,EVAR0.00.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0YearsFIGURE 74 Proportions surviving each year free from aneurysm-related death and all-cause death estimated in the decision model fora patient aged 75 years with a large AAA (6.5 cm) and poor fitness.not find aneurysm size to be a risk factor, perhapsbecause of the relatively few events. The base-casemodel used this regression to predict the rateof readmission after EVAR to be about 10% perpatient-year in the first 6 months, declining to< 2.5% per year by 5 years (Figure 75).Chapter 3 reported that the treatment effect HRfor reinterventions (EVAR relative to open surgery)was 2.7 (95% CI 1.8 to 4.1), but this includesreinterventions in the primary admission, 43the costs of which are included in the averageprocedure cost. The estimated HR for readmissionsafter EVAR compared with open repair usingan intention to treat analysis was 6.75 (SE 2.56)(Table 63). This is consistent with the proportionof patients with aneurysm-related reinterventionsfound by Schermerhorn et al. 96 at 4 years (9.1%after EVAR and 1.7% after open repair). However,this may overestimate the relative risk of EVARfor two reasons. First, EVAR trial 1 did not recordlate reinterventions for laparotomy. Schermerhornet al. 96 estimated that 4.7% of patients hadlaparotomy-related reinterventions 4 years afterEVAR and 9.7% after open repair. Second, vascularsurgeons may now be less inclined to reintervenefor some types of complication, such as type2 endoleak. The data presented in Chapter 3indicate that about 35% of interventions afterEVAR were for type 2 endoleak. As the EVAR trial 1TABLE 63 Results of Weibull survival model of the rate of readmission following aneurysm repair, using individual patient data from theEVAR trial 1. Patients are followed up within randomised groups after discharge from the primary procedure (equation 4 in Figure 69)Number of observations 1050Number of readmissions 62Patient-months (patient-years) 29,415 (2451)Coefficient SE Hazard ratio aEVAR intervention 1.91 0.38 6.75Constant –6.12 0.43Log (shape parameter) –0.53 0.001a The hazard ratio is the exponential of the coefficient.109© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidence0.12Rate of readmission/year0.100.080.060.04EVAR – EVAR trial 1EVAR extrapolatedOpen – EVAR trial 1Open extrapolated0.020.00 2 4 6 8 10 12 14 16YearsFIGURE 75 Predicted rates of readmission per year over time (Weibull regression, Table 63, EVAR trial 1 data). Dashed lines show therates of readmission predicted beyond the maximum 4-year follow-up available in EVAR trial 1.110represents our best estimate of recent UK practice,we use an HR of 6.75 as the base case but explorethis with sensitivity analyses.Resource use and costsCosts are incurred in the model during the primaryadmission, during surveillance post surgery andif the patient is readmitted to hospital for ananeurysm-related complication.Costs and resource use during the primary proceduresThe costs and resources used in the primaryprocedure are shown in Table 64 for the base-casemodel. Expected resource use in both proceduresis estimated from intention to treat analysis ofthe EVAR trial 1. 43,106 As these data are the meanfor all of the patients in the trial they include theexpected costs of in-hospital complications andmortality. It is possible that, given the evolutionof devices and procedures, these data do notrepresent current practice compared with theperiod 1999–2003 when the trial was recruiting.Chapter 3 found that the mean total length ofstay reported in the most recent registry datawas 13 days after open repair 16 and 6 days afterEVAR, 54 considerably less than in the EVAR armof the EVAR trial 1. 43 However, the EVAR trial1 data represent the best available randomisedcomparison of resource use in the UK and sowere used for the base case. A postal survey ofUK hospitals was conducted in January 2008 toinvestigate whether length of stay has changedsince the EVAR trial 1. The results are presentedin Appendix 3. The survey found that length ofstay may be currently lower after both EVAR andopen repair than in EVAR trial 1, and that thedifference in length of stay in general wards maynow be greater than that estimated by EVAR trial1. This scenario was explored in sensitivity analysis.It is likely that costs will depend on the riskcharacteristics of the patient, for example EVARtrial 2 46 found that these high-risk patients usedslightly more hospital resources than patients inthe EVAR trial 1. However, the base case assumedthat the difference in costs between EVAR and openrepair was constant for all patient groups. Chapter1 presents the list prices of each of the EVARdevices included in this review, when known.Intensive care during the primary procedureIn the base case, resource use and costs arebased on the actual use of intensive care andhigh dependency units as recorded by the EVARtrial 1. 43 There is no evidence from the survey inJanuary 2008 that the EVAR trial 1 underestimatesthe difference between EVAR and open repair inpatients’ length of stay in intensive care facilities(see Appendix 3). However, mean length of staymay not represent the full opportunity cost of thesefacilities, because some centres require an intensivecare bed to be available before commencinga procedure, in case it is needed. The surveyresults in Appendix 3 show that 86% of surgicalteams would cancel an open repair procedureif an intensive care unit bed was not availablecompared with 22% who would cancel an EVAR

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 64 Costs and resources used in the primary procedureCost (£)Resource useEVAROpenrepairEVAROpenrepairUnit cost(£) SourceDuring the primary procedureTheatre time(minutes)1593 1794 182 205 525 ISD Scotland; theatreservices R142X 147Preoperative days 467 541 1.9 2.2 246 NHS reference costs2006/7; QZ01A 148ICU days 947 3247 0.7 2.4 1353 NHS reference costs2006/7; XCO5ZTHE 148HDU days 593 1252 0.9 1.9 659 NHS reference costs2006/7; XC05ZHDU 148Ward days 1697 2263 6.9 9.2 246 NHS reference costs2006/7; QZ01A 148Blood (ml) 105 575 164 896 289 National BloodService 149Contrast (ml) 14 0 195 6 3.5 Medtronic 127Total costof primaryprocedure10,416 9893Conversion toopen repairduring primaryprocedure42,067 EVAR trial 1, 43 Epsteinet al. 106Subsequent to primary procedure (EVAR or open repair)Readmission 5936 EVAR trial 1, 43 Epsteinet al. 106Outpatient visit 83 NHS reference costs2006/7; speciality 107 148ComputedtomographyHDU, high dependency unit; ICU, intensive care unit.108 NHS reference costs2006/7; RA10Z 148procedure. This requirement might be a reason forthe longer average waiting time for open repairexperienced by patients in EVAR trial 1. As wellas longer waiting times for aneurysm surgery, thisrequirement might also affect patients waiting forother surgical procedures as there is a shortage ofcapacity of intensive care facilities in many surgicalcentres in the UK.Surveillance post surgeryAll patients undergoing EVAR, whether theyexperience adverse events or not, are assumedto require regular specialist hospital outpatientattendances and CT scans to monitor theiraneurysm repair. In the base case, based on the© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.results of a survey of UK hospitals participatingin the EVAR trials, 43 it was assumed that patientsrequire two surveillance visits during the first yearand one visit per year thereafter. Patients who haveopen repair require only one visit in the first yearand none thereafter. 106 A survey was undertaken inJanuary 2008 to update this information as part ofthis review (Appendix 3), which showed that theseassumptions are broadly typical of current practice,although the frequency of surveillance tends todiminish with time.Health-related quality of lifeChapter 3 reported the EVAR trial 1 results, whichshowed that HRQoL measured by EQ-5D tended111

Assessment of cost-effectiveness evidenceto decline in the first 3 months after randomisationbut by less after EVAR, with a difference in HRQoLin favour of EVAR after 3 months of 0.05 (SE0.02). 43 HRQoL recovered by 3–12 months andthere was no significant difference between thegroups. Based on these findings the base caseassumed that HRQoL declined by 0.077 in the6-month period following open surgery and by0.027 following EVAR. Patients without the needfor reinterventions were assumed to recover toage- and sex-specific average population values ofHRQoL 6 months after the procedure. Other utilityvalues used in the model are shown in Table 65.Cost-effectiveness analysisStandard decision rules were followed for thecost-effectiveness analysis using expected costsand QALYs. 151 When there are two options undercomparison, the ICER is calculated if both the costand the benefits of EVAR exceed those of openrepair. If EVAR is more costly but less effective thanthe alternative then EVAR is dominated and noICER is calculated.The same decision rule can be expressed in termsof maximising ‘expected net benefit’. 152 Expectednet benefit (NB) for a treatment option is definedas:NB (λ) = λ × QALYs – costswhere λ is the threshold cost-effectiveness used bythe decision-maker. This is the most convenientdecision rule when there are three or moremutually exclusive strategies being compared, asis the case in the subsequent section in which wecompare open surgery, EVAR and watchful waiting.Results are shown for thresholds of £20,000 and£30,000 per QALY.The results of the decision model are shown (1) forthe aggregate UK population who are consideredsuitable for aneurysm repair and (2) disaggregatedaccording to age group, aneurysm size andoperative fitness. Appendix 6 explains how themean characteristics of the UK population weredetermined.One-way sensitivity analyses were carried outby varying key parameters in the model. Aprobabilistic sensitivity analysis, based on theuncertainty in all of the parameters of the model,was undertaken to estimate the probability thatEVAR is more cost-effective than open repair as afunction of the threshold ICER. 153Table 66 shows the uncertainty arising frommeasurement error in the estimates of each ofthe parameters used in the base-case modelcomparing EVAR and open repair. Someparameters have been estimated from regressionequations (equations 1–4) and therefore there maybe correlations between the coefficients of theseequations. The Cholesky matrix was estimatedfor each risk equation and used to calculate thedistribution of the linear predictor for theseparameters, assuming that the coefficients of theseequations follow a joint normal distribution.Results of York economic assessment:EVAR compared with open repair forpatients with a large aneurysm (5.5 cm ormore) and assessed as fit for open repairResults for aggregate populationTable 67 shows the results of the decision model forthe average UK population.In the base-case analysis, the total incrementallifetime cost of EVAR versus open repair isTABLE 65 Health-related quality of life (HRQoL) values used in the modelMeanSourceMore than 6 months after successful surgeryAge ≤ 75 years 0.78 Kind et al. 150Age > 75 years 0.75 Kind et al. 150Loss of utility for 0–6 months after a procedureEVAR procedure 0.027 EVAR trial 1 43Open procedure 0.077 EVAR trial 1 43After readmission 0.077 Assumption112HRQoL or utility is an index measure of morbidity on a scale of 1 (good health) to 0 (death) with negative utilities feasible.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 66 Probability distributions for the parameters used in the probabilistic sensitivity analysis, for a 75-year-old patient with ananeurysm of 6.5 cm and of moderate fitnessParameter Value Mean SE Alpha Beta DistributionRisk equation(if applicable)SourceOperative mortalityProbability operativemortality EVAROdds ratio EVAR vs openrepairConversion to openrepair in primaryadmissionNon-AAA deathHazard ratio AAApopulation vs generalpopulationAll-cause hazard ratioafter EVAR vs open repairLate AAA deathHazard ratio (EVAR vsopen repair)Late AAA death (deaths/year)Resource useCost difference EVAR lessopen repair (£)Hazard ratio forreinterventions (EVAR vsopen repair)0.021 Joint normal(Cholesky)Equation 1 EUROSTAR 540.35 –1.05 0.373 Log-normal Meta-analysis,chapter 30.008 4 496 Beta EVAR trial 1 432.452 Joint normal(Cholesky)Equation 2 EUROSTAR 541.072 0.070 0.160 Log-normal EVAR trial 1 431.5 0.41 0.38 Log-normal Expert opinion0.009 Joint normal(Cholesky)Equation 4 EUROSTAR 54523 523 230 Normal EVAR trial 1 436.753 1.910 0.380 Log-normal EVAR trial 1 43£2002. This can be approximately broken downas the additional cost of the initial procedure(£520), conversions to open repair (£250), latereinterventions (£820) and the additional cost ofsurveillance (the remainder, about £410). The totaldifference in lifetime QALYs between EVAR andopen repair is estimated to be 0.041. The positivebenefit of EVAR is maintained as a cumulativeQALY gain of 0.056 up to about 3 years, but issubsequently offset by extra late aneurysm-relateddeaths and reinterventions in the long term afterEVAR. The ICER for the base case is approximately£49,000 per QALY (calculated as 2002/0.041).The model includes an excess hazard of late nonaneurysm-relateddeath after EVAR until thesurvival curves converge. If the excess hazard is setsuch that the survival curves converge at 8 years(with other parameters as the revised base case)then the ICER is approximately £22,000 per QALY.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.If the excess hazard is twice that of the base casethen the survival curves converge at 2 years and theICER is approximately £96,000 per QALY.The revised base case assumes that the hazard oflate aneurysm-related death is 1.5 times greaterafter EVAR than after open repair, for the lifetimeof the patient. If there is no difference (HR of 1)then the ICER is £29,000 per QALY. If the HRis 1.2, the ICER is approximately £37,000 perQALY. The HR may be time varying, for examplethere may be no excess hazard after 4 years. Thisscenario gives similar results to the revised basecase, with an ICER of approximately £49,000 perQALY.The original base case in the assessment reportassumed that the HR of late reintervention was6.7 for the lifetime of the patient, although theabsolute rate of reintervention is declining over113

Assessment of cost-effectiveness evidence114time and is low (about 2% per year) 4 years afterEVAR (see Figure 75). If there is no differencebetween treatments (HR of 1) the ICER isapproximately £27,000 per QALY. If the HRis 1.5 (corresponding to the relative hazard ofreinterventions for any cause in Schermerhorn etal. 96 ) the ICER is £29,000 per QALY.The original base case assumed that one follow-upappointment per year with CT was required afterEVAR. If the cost per year was half of this thenthe ICER is £44,000 per QALY. If there are nofollow-up visits (with reinterventions and aneurysmdeaths remaining unchanged) then the ICER isapproximately £39,000 per QALY.There may be a correlation between follow-upvisits, reinterventions and late aneurysm-relateddeaths. In a favourable scenario, if there are fewercomplications after EVAR, with less need for followup,fewer reinterventions and fewer aneurysmrelateddeaths, then the ICER is approximately£24,000 per QALY.If the OR of operative death is 0.25 rather than0.35 as used in the base case then the ICER isapproximately £22,000 per QALY, with otherparameters as in the revised base case. The survivalcurves take 4.5 years to converge, as the initialbenefit from EVAR is larger.The base case assumed that the EVAR procedurecost £523 more than open repair. We conducteda sensitivity analysis with a lower cost for theEVAR procedure, for example reflecting less useof intensive care than in the EVAR trial 1. If itis assumed that EVAR costs £623 less than openrepair, the ICER is approximately £21,000 perQALY. If it is assumed that EVAR costs the same asopen repair, the ICER is £36,000 per QALY. In amultivariate sensitivity analysis, if EVAR costs thesame as open repair and the costs of interventionand follow-up are lower than in the base case thenthe ICER is £12,000 per QALY.We also conducted a probabilistic sensitivityanalysis using the distributions shown in Table 66.The results are shown in Table 67. The probabilitythat EVAR is cost-effective in the base case is0.261 at £20,000 per QALY or 0.424 at £30,000per QALY. At a threshold willingness to pay of£20,000 per QALY, EVAR is more likely to be costeffectivethan open repair under some scenarios:if the survival curves do not converge; if the HR ofreintervention is 1.5 and the annual surveillancecost of follow-up is low; if the OR of operativemortality is 0.25; or if the EVAR procedure costsless than open repair. It may seem counterintuitivethat in some scenarios the ICER (the measure ofmean cost-effectiveness) is greater than £20,000but the probability that EVAR is cost-effectiveis more than 50% (the measure of median costeffectiveness)at a threshold of £20,000 per QALY.This occurs because the Markov model is nonlinear,and the distribution of net benefits is notsymmetrical over all of the simulations of theprobabilistic sensitivity analysis.Base-case results disaggregatedby patient subgroupTable 68 shows the cost-effectiveness results forEVAR compared with open repair by age, aneurysmsize and fitness at baseline. The results of the basecasemodel suggest that EVAR is cost-effective forpatients of relatively poor fitness at most ages andaneurysm sizes. For patients with relatively goodfitness (i.e. no comorbidity) open repair is morecost-effective. Note that the result for patientswith moderate fitness, aged 75 years and with ananeurysm of 6.5 cm corresponds to the averageresult shown in Table 67.In general, the ICER of EVAR versus open repair islower for older patients than for younger patients,for patients with a larger aneurysm size than witha smaller aneurysm size, and for patients of poorerfitness than of better fitness (Table 68). Olderpatients and those with larger aneurysms andpoorer fitness face increased operative mortality.The model assumes that the relative treatmenteffect (OR) of operative mortality is constantacross risk groups. Therefore, the absolute benefitof EVAR compared with open repair is greater inpatients of poorer operative risk. Furthermore,there is a long-term risk of complications andreinterventions after EVAR. Patients with a longerlife expectancy face a greater cumulative risk ofcomplications, with additional costs, disutility andrisk of late aneurysm-related mortality.The ICER comparing EVAR and open repair doesnot decrease in a linear progression with age (Table68). For example, for a patient with moderatefitness and aneurysm size of 6.5 cm, the ICER is£92,000 per QALY at age 70 years, £49,000 perQALY at age 75 years and £33,000 per QALY atage 80 years. This occurs because the ICER is aratio of the difference in costs to the differencein health benefits and increases rapidly as thedifference in the denominator approaches zero.The lifetime difference in costs is similar for allage groups (about £2000) whereas the lifetime

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48difference in QALYs is only 0.025 in 70-year-oldsbut 0.052 in 80-year-olds, because the absolutedifference in operative mortality is greater forolder patients.There is a non-linear relationship betweenaneurysm size and operative mortality. TheEUROSTAR data predicted that the risk of lateaneurysm-related death after EVAR increaseswith aneurysm size at the time of the procedure(equation 3, Table 62), confirming estimates madeby studies on earlier EUROSTAR data sets. 82 Theincreased risk of late aneurysm-related deathcauses the ICER of EVAR versus open repair to begreater for patients with an aneurysm size of 6.5 cmthan for patients with an aneurysm size of 6 cm(Table 68).Table 68 shows that EVAR might also be costeffectivecompared with open repair in olderpatients (80 years or more) with moderate fitnessand very large aneurysms (≥ 7.5 cm). Althoughwe define fitness in this analysis as ‘moderate’ ifpatients have few pre-existing conditions relativeto other patients of their age, operative mortalitywould be high in absolute terms for these patients,estimated at 6.7% after EVAR and 17% afteropen repair. A policy of no surgery or watchfulwaiting should also be considered for patientswith high expected operative mortality, comparedwith the risk of rupture without surgery. Thesepolices will be evaluated in the model comparingimmediate elective surgery, watchful waiting and nointervention.The cost-effectiveness of EVARcompared with open repair in womenThe risk equations (equations 1–4) estimatedearlier in this section did not find gender to be asignificant explanatory variable, and therefore thebase-case model does not distinguish between maleand female patients, other than to use life tables formen to estimate non-aneurysm-related mortalityin the general population. However, Chapter3 identified one large study 86 that found anindependent effect of gender on 30-day operativemortality (OR women versus men 1.46, 95% CI1.26 to 1.68). A secondary analysis explored thecost-effectiveness of EVAR specifically in women,assuming greater 30-day operative mortality afterEVAR in women as estimated by Timaran et al. 86 ,assuming that the average treatment effect (OR)of 30-day mortality of EVAR compared with openrepair found by the RCTs in Chapter 3 applies towomen and using the age-specific non-aneurysmrelatedmortality rates (life tables) for the female© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.general population. Results were very similar tothose of the base case.Comparison of York modelwith Medtronic model ofEVAR versus open repairThe Medtronic model comparing EVAR and openrepair was described earlier in this chapter (seeSystematic review of existing cost-effectivenessevidence). The main differences between the Yorkbase-case model and the Medtronic 127 base-casemodel are:• the difference between EVAR and open repairnon-aneurysm-related mortality rates in themedium term• the difference in late aneurysm-relatedmortality• the hospital costs (intensive care and operatingtheatre time) of the EVAR procedure• the relative rate of reinterventions.The assumptions made by Medtronic 127 are shownas scenario 18 in Table 67. In this scenario thereis a slower rate of convergence of the survivalcurves than in the York base case, a lower relativecost of EVAR and no difference in late aneurysmrelateddeaths between EVAR and open surgery.The Medtronic model presented results for apatient aged 70 years with an aneurysm size of≥ 5.5 cm. Fitness was unspecified in the Medtronicmodel (i.e. results were for the average level offitness of patients in the EVAR trial 1). When theseassumptions are used in the York model the ICERis about £15,000 per QALY, consistent with theresults reported in the Medtronic report. 127Figure 76 illustrates the differences between theassumptions for all-cause mortality made in theYork model and in the Medtronic model. Thefigure shows the difference in cumulative deathsbetween EVAR and open repair predicted bythe models. The York model assumed that theinitial survival advantage of EVAR for operativemortality would be entirely offset within 3 yearsby a relatively higher non-aneurysm-relateddeath rate after EVAR. This scenario is consistentwith the results of EVAR trial 1, DREAM and alarge US matched-cohort study. 96 The predictedsurvival curves are shown in Figure 77 for a patientaged 70 years with an aneurysm size of 5.5 cm.Furthermore, the York model assumed that therewould be a small but persistent difference betweenthe treatments in the rate of late aneurysm-relateddeaths. This scenario is consistent with the longtermEUROSTAR data. 82 In contrast, the base-case115

Assessment of cost-effectiveness evidenceTABLE 67 Results for the base-case and sensitivity analyses for the average UK population suitable for EVAR or open surgeryNo.Description of scenarioParametersHazardratio for lateaneurysmdeaths1. Base case 1.5 1.0722. No difference in late non-aneurysm mortality: survival curves do not converge 1.5 1.0003. Very small difference in late non-aneurysm mortality: very slow rate of1.5 1.010convergence of the survival curves4. Small difference in late non-aneurysm mortality: slow rate of convergence of the 1.5 1.030survival curves5. Larger difference in late non-aneurysm mortality: faster convergence of the 1.5 1.144survival curves6. No difference in late aneurysm mortality 1.0 1.0727. Lower HR of late aneurysm mortality (HR = 1.2) 1.2 1.0728. No difference in aneurysm mortality after 4 years (HR = 2.46 from 30 days to Time varying 1.0724 years and HR = 1 thereafter)9. Half the yearly cost of follow-up after EVAR 1.5 1.07210. No follow-up beyond first year after EVAR or open repair 1.5 1.07211. No difference between treatments in late reinterventions 1.5 1.07212. Lower HR of late reinterventions 1.5 1.07213. Lower cost of follow-up and lower rate of reintervention than in base case 1.5 1.07214. Odds ratio of operative mortality is 0.25 not 0.35 1.5 1.07215. EVAR procedure costs £1100 less than in base case (e.g. less use of ITU), i.e. £623 1.5 1.072less than open repair instead of £523 more than open repair)16. EVAR procedure costs same as open repair 1.5 1.07217. EVAR and open repair procedure costs are equal, with lower cost of follow-up 1.5 1.072and lower rate of reintervention than in base case18. EVAR procedure costs £623 less than open repair, fewer reinterventions than inbase case, lower rate of excess mortality after EVAR (Medtronic model)a1.055HR, hazard ratio; P(20K)/P(30K), probability that EVAR is cost-effective at £20,000/£30,000 per QALY.a In this scenario there is an excess rate of mortality for any cause (HR = 1.055) for 4 years after EVAR. There are noadditional late aneurysm deaths. There is no excess mortality after 4 years, and the survival curves do not meet.Excess nonaneurysmmortalityafter EVAR116model of Medtronic assumed a more optimisticscenario, that the rate of convergence of thesurvival curves would be slightly slower and thatthe survival curves would not meet. There would beno further difference in deaths beyond 4 years and,therefore, a slight long-term difference in survivalwould be maintained in favour of EVAR over thelifetime of the patients (Figure 76). The predictedsurvival curves when the Medtronic assumptionsare used in the York model are shown in Figure 78.Comparison of York model with otherpublished economic evaluationsThe base-case model found that EVAR was notexpected to be cost-effective on average, but wascost-effective for patients with poorer fitness. Theseresults can be compared with the published modelsfor similar patient groups. The systematic reviewof existing cost-effectiveness evidence presentedearlier in this chapter found that the studies byMichaels et al. 107 and Epstein et al. 106 were thepublished economic evaluations most relevant tothe current decision in England and Wales. JAMichaels, DM Epstein and MJ Sculpher are authorsof one or both of these published papers and alsoof this report.Both Michaels et al. 107 and Epstein et al. 106concluded that EVAR was not expected to be costeffectivein patients eligible for elective sutgery.However, there were differences between these

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Cost/yearof follow-upvisits (£)Hazardratio for latereinterventionModel predictionsYears toconvergenceof survivalcurves ΔQALY ΔCost (£)ICER (£/QALY) P(20K) P(30K)108 6.7 3.0 0.041 2002 48,990 0.261 0.424108 6.7 Lifetime 0.107 2023 18,873 0.621 0.720108 6.7 8.0 0.090 2018 22,419 0.533 0.710108 6.7 5.0 0.067 2011 30,136 0.382 0.572108 6.7 2.0 0.021 1995 96,085 0.13 0.247108 6.7 4.0 0.068 1999 29,276 0.338 0.539108 6.7 3.5 0.055 2001 36,553 0.291 0.477108 6.7 2.5 0.041 2005 48,567 0.249 0.42154 6.7 3.0 0.041 1798 43,988 0.296 0.4540 6.7 3.0 0.041 1593 38,987 0.341 0.513108 1.0 3.0 0.044 1187 27,184 0.490 0.627108 1.5 3.0 0.043 1259 29,010 0.437 0.58154 1.5 3.0 0.043 1052 24,227 0.581 0.686108 6.7 4.5 0.091 2000 21,922 0.542 0.688108 6.7 3.0 0.041 868 21,245 0.561 0.688108 6.7 3.0 0.041 1485 36,326 0.354 0.49754 1.5 3.0 0.043 534 12,305 0.738 0.81398 2.7 Lifetime 0.076 1098 14,506 0.654 0.788published models and the York model in theassumptions used to arrive at this conclusion.Michaels et al. found a greater long-term benefitin favour of EVAR than the York model, and agreater difference in costs, but this study waspublished before the mid-term results of the goodqualityRCTs were available. The study by Epsteinet al. was published after the mid-term resultsof the RCTs were available, and based on thesetrial results assumed that the survival curves forEVAR and open repair would meet by 4 years. Thepublished model has been adapted for use in theYork economic evaluation. The main difference inthe parameter values between the models is thatEpstein et al. assumed a greater difference in lateaneurysm-related deaths (HR EVAR versus openrepair = 6.0) than in the York model (HR = 1.5).The York model also used regression analysis toestimate baseline risks of operative mortality, lateaneurysm-related mortality and non-aneurysmrelatedmortality in a wider range of patient groupsthan in Epstein et al.The next section extends the York model tocompare the cost-effectiveness of EVAR, openrepair, watchful waiting and no intervention.117© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidence118TABLE 68 Base-case and sensitivity analyses showing ICERs comparing EVAR and open repair for patients of different fitness, aneurysm size and ageFitnessGood Moderate PoorAge (years)70 75 80 85 70 75 80 85 70 75 80 85AAA(cm)ScenarioBase case 5.5 1,120,563 215,306 96,902 62,817 79,539 53,000 38,006 28,181 27,658 21,442 17,354 14,6046.5 Dom 2,918,114 132,053 59,579 91,947 48,990 32,801 24,959 23,267 17,954 14,857 13,1317.5 Dom 138,913 63,775 37,757 44,264 29,560 21,816 17,248 15,168 12,313 10,669 9855Lower cost of followup5.5 178,616 76,951 43,055 31,317 33,486 24,572 19,272 15,568 13,108 10,939 9588 8724and lower rate ofreinterventions6.5 Dom 338,899 61,553 31,980 40,766 24,227 17,735 14,631 11,615 9666 8670 82647.5 Dom 60,551 31,961 20,810 20,795 15,014 12,002 10,253 7686 6714 6299 6274Odds ratio of operative 5.5 129,313 70,922 46,805 33,019 35,001 26,132 19,819 15,627 14,188 11,506 9647 8533mortality 0.25 not 0.356.5 346,307 77,388 43,933 28,413 31,102 21,922 16,737 13,499 11,602 9626 8418 78787.5 74,231 38,924 25,945 18,974 18,792 14,233 11,441 9710 7978 6876 6273 6146Lower cost of followup,5.5 107,229 43,213 22,396 15,019 19,277 13,115 9457 7020 7183 5510 4412 3682lower rate ofreinterventions and equal6.5 Dom 181,687 30,406 14,545 22,467 12,305 8252 6258 6069 4619 3776 3307cost of procedures 7.5 Dom 32,405 15,749 9434 11,436 7602 5561 4361 4001 3192 2724 2483Key: Dark grey shading, ICER > £30,001 per QALY or EVAR dominated; light grey shading, £20,001 per QALY < ICER < £30,000 per QALY; unshaded, ICER < £20,000 per QALY.The ICER is the difference in expected costs/difference in expected QALYs. Dominated (Dom) means that EVAR has less expected benefits and higher costs than open repair.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Difference in cumulative hazard of death by year t0.050.040.030.020.010.00–0.01–0.02–0.03Difference in cumulative deaths for all causes, York base caseDifference in all-cause deaths, Medtronic base-case model2 4 6 8 10 12 14Years(t)FIGURE 76 A comparison of the difference in cumulative deaths between EVAR and open repair over time for a patient aged 70 yearswith an aneurysm size of 6.5 cm and moderate fitness predicted by (a) the York model and (b) the Medtronic base-case model.1.00.90.80.7Survival0.60.50.40.30.20.1AAA cause EVARAAA cause openAll-cause death EVARAll-cause death open0.00.0 1.0 2.0 3.0 4.0 5.0 6.0YearsFIGURE 77 Predicted survival curves from the York model for a patient aged 70 years with moderate fitness and an aneurysm size of6.5 cm. Survival curves converge by 3 years.Model comparing immediateelective surgery, watchfulwaiting and no interventionMethods of model comparingsurgery and watchful waitingIntroductionThe objective of this second model was to broadenthe nature of the comparisons made using the first© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.model. Specifically, the second model considerswhen surgery (with EVAR or open repair) mightbe cost-effective compared with no surgery ordelaying the decision. The model brings togetherthe sparse available evidence about natural historyin untreated patients with evidence in treatedpatients to predict outcomes of a wide range ofmanagement policies in patients with diagnosedaneurysm. Given the uncertainties in these data,119

Assessment of cost-effectiveness evidence1.00.90.80.7Survival0.60.50.40.30.20.1AAA cause EVARAAA cause openAll-cause death EVARAll-cause death open0.00.0 1.0 2.0 3.0 4.0 5.0 6.0YearsFIGURE 78 Predicted survival curves using Medtronic assumptions in the York model for a patient aged 70 years with moderate fitnessand an aneurysm size of 6.5 cm. Survival curves do not converge. There is a small but cummulatively important difference in all-causesurvival between the treatments.120the model is intended to be exploratory andsuggest areas for further research.Current guidelines for the management of AAAwere discussed in Chapter 1. Briefly, patientsare observed until the aneurysm reaches 5.5 cmin diameter, after which surgical intervention isconsidered. 141 Patients considered fit for opensurgery might be offered EVAR or open surgery;patients considered unfit for open surgery mightbe offered EVAR or no intervention. However, inpractice there is a continuous range of probabilitiesof operative mortality and the optimummanagement policy should systematically weighup all of the risks to the patient – that is, operativemortality and late mortality if treated versus therisks of rupture if untreated. 11 Furthermore, apublicly funded health-care system must alsoevaluate the use of health-care resources, whichis not considered explicitly by the current clinicalguidelines. This section presents a decision modelto evaluate the cost-effectiveness of surgery,watchful waiting or no surgery for patients ofdifferent ages, operative fitness and aneurysm size.Description of the watchfulwaiting strategyAt each consultation with the vascular surgeon thepatient faces four options:• immediate elective surgery with EVAR• immediate elective surgery with open repair• ruling out surgery entirely• delaying the decision (watchful waiting).We assume that the patient is evaluated every6 months in the watchful waiting policy 146 andthat the patient attends all scheduled follow-upvisits. In practice, a substantial risk of patientnon-compliance would diminish the value of awatchful waiting strategy, although we do notmodel this scenario. We assume that surveillanceis discontinued if a decision is made to rule outsurgery and there are no subsequent monetarycosts to the health-care service. In practice, thepatient may return if the aneurysm becomessymptomatic, but we do not model this scenario.The benefits of delaying the decision are that itallows more information on the aneurysm growthrate to be assembled, and preserves the option tocommence immediate surgery in the future shouldthe patient’s health state (aneurysm size) worsen. 10The costs of deferral are monetary costs (themonitoring costs of CT and outpatient attendance)but also an important opportunity cost: patientsmay die from rupture while waiting. Waiting isalso a source of uncertainty: people prefer currentbenefits rather than future benefits. We representthe cost of this impatience by discounting delayedbenefits. Because AAAs are usually asymptomaticwe assume that patients have normal HRQoL fortheir age while under surveillance, although thereis some evidence that patients with diagnoseduntreated aneurysm suffer anxiety. 146

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48The approach used to model watchful waiting is asfollows:• first, the model previously described toevaluate EVAR versus open surgery was used toestimate the maximum expected net benefit ofsurgery in patients of a given fitness for a rangeof aneurysm sizes (4–8 cm, in increments of0.5 cm) and ages (70–85 years, in increments of6 months)• second, another model was constructed toevaluate an option of no surgery (i.e. naturalhistory, with no treatment and no surveillance)for the same patient groups; this model isdescribed in the following section• finally, a dynamic programme was constructedusing these data to estimate the net benefit ofa watchful waiting strategy and to calculate theoptimum policy (EVAR, open repair, no surgeryor watchful waiting) for each aneurysm size andpatient age.Model to estimate the naturalhistory of untreated aneurysmTo estimate the natural history of untreatedaneurysm a Markov cohort model is used. The aimof the model is to estimate QALYs over a patient’slifetime if the patient is left untreated. As thereis no surveillance and no surgery in this modelthere are no costs. The discrete health states areaneurysm size, from the size at diagnosis up to amaximum of 10 cm in diameter in increments of0.5 cm. Rupture rate is conditional on aneurysmsize. The mean growth rate and standard deviationand rupture rate were obtained from a review ofthe literature on the natural history of untreatedaneurysm. It was assumed that the growth rateof aneurysms (g) is normally distributed with themean and variance being a function of aneurysmsize in the previous period. Markov transitionprobabilities for moving from one health stateto another were derived from this continuousdistribution as follows:• Pr(aneurysm increases by 1 cm in a single6-month period) = Pr(g ≥ 1)• Pr(aneurysm increases by 0.5 cm in a single6-month period) = Pr(0.5 ≤ g < 1)• Pr(no change in aneurysm in the 6-monthperiod) = Pr(g < 0.5)• It is assumed that aneurysms do not diminishin size.As the annual probability of rupture is estimated tobe 90% for aneurysms of 10 cm in diameter 11 it wasassumed unnecessary to predict growth beyond this© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.size. Consequently, when the aneurysm is 9.5 cm indiameter the above algorithm is amended to:• Pr(aneurysm increases by 0.5 cm in a single6-month period) = Pr(g ≥ 0.5)• Pr(no change in aneurysm in the 6-monthperiod) = Pr(g < 0.5).In this model rupture is assumed to be fatal. Veryfew patients reach hospital alive after rupture andtherefore the possibility of emergency surgerywould be unlikely to affect the results. 11 Given theabsence of evidence on how fitness might evolveover time, and the effect of fitness on aneurysmgrowth and rupture, it is assumed that fitness isconstant over the duration of the model.Parameter estimation fornatural history modelRupture rate for untreated patientsUntreated patients face a risk of rupture of theiraneurysm (Table 69). It is difficult to measure therisk of rupture in an untreated patient becausethe natural history is rarely fully observed.Interventions might be considered when therisks of rupture outweigh the operative risk andtherefore censoring is not at random. Powell et al. 154conducted a review of the literature and comparedthe results with estimated rupture rates in theEVAR trial 2. The EVAR trial 2 is the only studywe know of that specifically measured untreatedrupture rates in patients suitable for EVAR.Powell et al. 154 found that the patients with largeaneurysms (> 6 cm) in the EVAR trial 2 had a loweruntreated risk of rupture than patients in otherstudies and concluded that this might be due to theEVAR trial patients being anatomically suitable forEVAR (Table 69). However, there were few patientswith further CT scans after randomisation andso growth after the baseline was not investigatedin the EVAR trial 2. This limits the usefulness ofthese data to model a watchful waiting strategy.For patients with aneurysms of < 6 cm they foundthat the rupture rate in EVAR trial 2 was similarto that in other published studies. Because of timeconstraints the data on rupture rates used in thismodel were not identified by a systematic reviewof the literature. However, we believe we haveidentified the most important sources of evidencerelevant to the UK (Table 69). We used the estimatesfrom Michaels 1992 11 as the base case as thesedata were available for a wide range of aneurysmsizes and appeared to be broadly consistent withestimates from the EVAR trial 2. 154 Rupture rateswere smoothed with respect to aneurysm size withan exponential function.121

Assessment of cost-effectiveness evidenceTABLE 69 Estimates of untreated rupture rates for different sizes of aneurysm: results from review of the literatureAAA diameter (cm)Rupture rate/yearStudies of patients considered fit for open surgeryLimet 1991 156 (case series, based on last observed AAA diameter) < 4 04–5 N/A> 5 0.22Michaels 1992 11 (meta-analysis, based on last observed AAA diameter) 3–3.9 0.0054–4.9 0.0105–5.9 0.0506–6.9 0.0907–7.9 0.1258–8.9 0.2509–9.9 0.50010+ 0.900Reed 1997 157 (case series, based on last observed AAA diameter) 3–3.9 0.0004–4.9 0.0105–5.9 0.1106+ 0.260UKSAT 1998 158 (surveillance arm of RCT) 4–5.5 0.010Kim 2005 159 (MASS trial, based on baseline AAA diameter) 3–4.4 0.0004.5–5.4 0.0095.5+ 0.063Studies of patients refusing or unfit for open repairPowell 2008 154 (meta-analysis of five studies, a based on baseline AAA 5.0–5.9 0.103diameter)≥ 6 0.270Powell 2008 154 (EVAR trial 2, based on baseline AAA diameter) 5.5–5.9 0.097≥ 6 0.174Studies of patients both fit and unfit for open repairBrown 2003 155 (Canadian cohort, men) 5.0–5.9 0.0100.141Brown 2003 155 (Canadian cohort, women) 5.0–5.9 0.039≥ 6 0.223Brown 1999 2 (UKSAT randomised and unrandomised, based on last 3–3.9 0.003observed or estimated AAA diameter)4–4.9 0.0155–5.9 0.065a The five studies used in the Powell review 154 were Jones 1998, 160 Brown 1999, 161 Conway 2001, 162 Lederle 2002 163 andAziz 2004. 164122Powell et al. 154 and Brown et al. 155 found that rupturerates tended to be greater in women for a givenaneurysm size, although Powell et al. found theresult to be non-significant [HR women versus men1.21 (95% CI 0.77 to 1.90)].Expansion rate of untreated aneurysmTable 70 shows the estimates of the expansion rateof untreated aneurysm from the literature review.Because of time constraints these data were notidentified by a systematic review of the literature.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 70 Expansion rate of untreated aneurysm: results of review of the literatureLimet 1991 156 (case series, based on lastobserved AAA diameter)AAA diameter (cm)Median expansionrate (cm/year)< 4 0.53 N/A4–5 0.69 N/A> 5 0.74 N/AVariabilityNo increase (%)Michaels 1992 11 (meta-analysis, based on last 3–3.9 0.28 53observed AAA diameter)4–4.9 0.60 225–5.9 0.68 196–6.9 0.96 57–7.9 1.26 0Reed 1997 157 (case series) All 0.21 N/AUKSAT 1998 158 (surveillance arm of RCT) 4–5.5 0.33 IQR 0.2–0.53 cmKim 2005 159 (MASS trial, based on baseline AAAdiameter)Rate of expansion tonext size in 3 months3–4.4 N/A 0.0254.5–5.4 N/A 0.087> 5.5 N/A N/AIQR, interquartile range.We used the mean expansion rate from Michaels 11as the base case as these data were available for awide range of aneurysm sizes and appeared to beconsistent with estimates from the other sources.Not all of the studies reported the standarddeviation or other measures of variability. Weestimated the standard deviation of the expansionrate to be 0.15 cm/6 months in aneurysms of4–4.4 cm, 0.30 cm/6 months in aneurysms of4.5–6.9 cm and 0.34 cm/6 months for aneurysms> 7 cm, which seemed roughly consistent with thedata on variability of the expansion rate estimatedby Kim et al., 159 UKSAT 158 and Michaels. 11 Table 71calculates the transition probabilities of movingfrom the current aneurysm size to one or two sizeslarger in one cycle of the natural history modelassuming a normal distribution and the meanexpansion rate from Table 70.Illustration of the predicted rate of mortality ofsurgical treatment compared with no treatment ateach age and aneurysm sizeFigure 79 illustrates the rate of mortality estimatedover time in the model for a patient with a startingage of 70 years, with poor fitness and with an initialaneurysm diameter of 4 cm. Without treatment theaneurysm is predicted to grow exponentially andthe risk of rupture increases according to aneurysmdiameter. 11 Given these estimates of aneurysmgrowth, and the risk equation estimated fromEUROSTAR (Table 58, equation 1), the expectedoperative mortality with EVAR would increase inrelation to increasing age and aneurysm diameter,from about 1.5% at age 70 years to 10% after 7years.Cost-effectiveness analysis usingdynamic programmingThis section describes how dynamic programmingwas used to select the most cost-effective option(surgery, no intervention or watchful wait) forpatients at each age and aneurysm size, using theresults of the models for estimating the net benefitsof surgery and the natural history described in theprevious sections. The methods are closely basedon the work of Driffield and Smith. 10This section has three parts:1. We explain the concepts of dynamicprogramming and how the method can be usedto simplify the modelling of watchful waiting.123© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidence124TABLE 71 Mean and standard deviation of expansion assumed in the base case per 6 months, and calculated transition probabilities of expansion in a 6-month cycle, assuming a normal distributionfor aneurysm growthAneurysm size at start of 6-month cycle (cm)4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10Mean and SD of expansion in 6 months (cm)Mean 0.24 0.28 0.34 0.40 0.48 0.57 0.67 0.80 0.96 0.96 0.96 0.96 0.96SD 0.15 0.30 0.30 0.30 0.30 0.30 0.35 0.35 0.35 0.35 0.35 0.35 0.35Probability of 0- to 0.5-cm growth, 0.5- to 1-cm growth and 1- to 1.5-cm growth in 6 monthsNo growth 0.96 0.77 0.71 0.63 0.53 0.41 0.31 0.19 0.09 0.09 0.09 0.09 10.5-cm growth 0.04 0.23 0.28 0.35 0.43 0.51 0.52 0.53 0.46 0.46 0.46 0.91 01-cm growth 0.00 0.01 0.01 0.02 0.04 0.07 0.17 0.28 0.45 0.45 0.45 0.00 0Note: The data on mean aneurysm growth with respect to aneurysm size from Michaels 11 have been smoothed using an exponential function.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48120.30AAA size (cm)108642AAA sizeRupture rate 6 monthsOperative mortality (EVAR)0.250.200.150.100.05Rate of rupture/6 monthsoperative mortality0 0.0070 70.5 71 71.5 72 72.5 73 73.5 74 74.5 75 75.5 76 76.5 77AgeFIGURE 79 Illustration of mean rates of operative mortality and rupture estimated over time in the model for a patient aged 70 years,with poor fitness and with an aneurysm of diameter 4 cm at diagnosis. The figure also shows the change in aneurysm size over time.2. We calculate the optimal policy for eachaneurysm size in the final time period.3. We calculate the optimal policy for eachaneurysm size in each of the previous timeperiods.Concepts of dynamic programmingFigure 80 illustrates the management options. Thebenefits and costs of the strategies of immediateelective repair versus no surgery depend only onfuture chance events, such as whether the aneurysmgrows slowly or quickly in each cycle, or the patientdies. The previous sections described the Markovmodels used to estimate patients’ lifetime expectedbenefits and costs for these two strategies, forany given starting age, aneurysm size and fitness.In principle, we could also use a decision treeor Markov model to calculate a watchful waitingstrategy. However, this would quickly becomeintractable. The watchful waiting strategy is morecomplex than a decision simply to treat or nottreat taken at diagnosis. At each future age andaneurysm size there are three decision options(immediate surgery, rule out surgery or watchfulwaiting) and an indeterminate time horizon. Theproblem is dynamic, i.e. the optimal strategydepends not only on future chance events but alsoon decisions made in the light of those events(Figure 80). This means that there are hundredsof possible strategies for watchful waiting (e.g.immediate EVAR, wait 6 months then surgery if theaneurysm is 0.5 cm larger, wait 1 year, etc.) for eachstarting age and aneurysm size.To reduce this complexity we use a dynamicprogramming formulation to calculate the© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.optimum strategy for each age and aneurysmsize. 165 Dynamic programming is based on asimple principle: that if a decision has a finitetime horizon (N periods) and we know the optimalchoices (payoffs) for each aneurysm size (modelstate) in period N+1 and we know the probabilitiesof transition between model states then we canwork backwards to induce the optimal choicesfor each model state in the previous period (N,N–1 and so on) until the starting period (t = 1).Both surgery and a decision to discharge thepatient are irreversible. Delaying a decisionmight have value because, as time progresses, theinformation regarding aneurysm size and growthrate is updated, resolving uncertainty and offeringthe option of changing the treatment policy.Continuing surveillance with an option to treat inthe future if the aneurysm grows might give greaterexpected benefit than either of the irreversibledecisions, which can be compared with the costsof obtaining this information. The output of thedynamic programme is a policy that states theoptimal management option for each patient ageand aneurysm size.Calculating the optimal policy for each aneurysmsize in the final time periodWe begin by assuming that there is a maximumaneurysm size, say 8 cm, above which we will notcontinue watchful waiting, that is, we will eitheroperate or discharge the patient. A size of 8 cm isarbitrary but as the risk of rupture at this size is25% per year, and expected growth is over 1¼ cmper year, 11 the expected benefits of surveillancebeyond this size would be very low. As we assumecontinued surveillance is not an option, the125

Assessment of cost-effectiveness evidenceImmediateelectiverepairSurvivesurgeryOperativedeathNo growthNo growthNo surgerySlow growthSlow growthFast growthFast growthRuptureRupture= decision= chance eventWatchfulwaitingprogrammeFirst periodNo growthSlow growthFast growthRuptureImmediateelectiverepairNosurgeryWatchfulwaitingSecond periodFIGURE 80 Management of a patient diagnosed with AAA, showing immediate elective repair, no surgery and watchful waitingstrategies.decision about whether to operate or discharge thepatient at any given age when the aneurysm is 8 cmdepends on whether the net benefits of surgeryare greater than no surgery; the incrementalnet benefits of surgery versus no surgery willdiminish with age (at a given aneurysm size) asoperative mortality increases and life expectancybeyond surgery falls. On the other hand, theincremental net benefits of surgery versus nosurgery will increase with aneurysm size (at a givenage) as the risk of rupture outweighs the risk ofoperative mortality. We compare the net benefitsof open surgery, EVAR and no surgery to find themaximum age at which it is no longer cost-effectiveto operate, even for aneurysms of 8 cm.Under the base-case model, at a willingness to payof £30,000 per QALY and assuming the ruptureand growth rates from Michaels, 11 for patients in‘very poor’ fitness (i.e. ineligible for EVAR trial 1)we find this age to be 80 years. That is, at age 80years and above it is never cost-effective to operate,whereas at age 79.5 years it is cost-effective tooperate on aneurysms of 8 cm but not on smalleraneurysms.Consequently, we need only consider watchfulwaiting up to age 79 years, as watchful waitingcan only be more cost-effective than offering notreatment if surgery is a possible future option.In this case N = 19 periods for a starting age inthe model of 70 years and a cycle length of 6months [(79–70) × 2 + 1 = 19]. Even though weonly consider watchful waiting up to age 79 years,net benefits of surgery and no surgery have beencalculated for a lifetime using the Markov modelsdescribed in previous sections. Note that thismaximum age is a function of willingness to payand the fitness of the patient, as well as all of theparameters of the decision model.Calculating the optimal policy for each aneurysmsize in each of the previous time periodsGiven that we have calculated the optimum choicesfor each health state (aneurysm size) at periodN + 1 (corresponding to age 79.5 years) we usebackward induction to calculate the optimumchoices for each health state in the previous periodN. Figure 81 illustrates the numerical solutionmethod with a segment of the decision tree for apatient of very poor operative fitness, for example126

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 485.5 cm:Defer = –191Treat = 8597Abandon = 06 cm:Defer = –191Treat = 7259Abandon = 06.5 cm:Defer = –191Treat = 5095Abandon = 07 cm:Defer = 37Treat = –1593Abandon = 07.5 cm:Defer = 896Treat = 888Abandon = 08 cm:Defer = 1151Treat = 1366Abandon = 0Period N79 yearsPeriod N + 179 years5.5 cm:Treat = –9166No treat = 06 cm:Treat = –7661No treat = 06.5 cm:Treat = –7071No treat = 07 cm:Treat = –3954No treat = 07.5 cm:Treat = –1152No treat = 08 cm:Treat = 1366No treat = 0FIGURE 81 Illustration of the dynamic programme decision tree for the periods N and N + 1 for a patient of very poor operative fitness.The values shown are the incremental net benefits of deferring the decision (watchful waiting) or of immediate treatment compared withabandoning watchful waiting (never offering surgical treatment). The dynamic programme is evaluated from right to left, that is, thecost-effective policies are identified for each state in period N + 1and then for each state in period N, N – 1, etc. Note: The cost of anoutpatient visit with CT scan is £191. The probability of the aneurysm growing from 7 to 8 cm in 6 months is 0.17 and of growing from7.5 to 8 cm in 6 months is 0.52. Cost-effective options at a threshold of £30,000 per QALY are highlighted in bold.ineligible for EVAR trial 1 or the DREAM trial. Thewillingness to pay threshold is £30,000 per QALY.The right-hand side of the figure shows thepossible states of health in period N + 1 (age 79.5years). The incremental net benefits of surgery(most cost-effective of EVAR versus open repair)compared with no surgery have been calculatedusing the decision models for treated anduntreated patients previously described; the valuefor no surgical treatment is always shown as zero(relative to surgery). In the period N + 1 there isno option to defer and so the decision is merelywhether the patient should receive treatment.This decision is straightforward (given the data),depending only on whether the incrementalnet benefits of surgery are positive (relative tono surgery). At age 79.5 years surgery would beoffered only if the aneurysm is 8 cm in diameter.Moving back to period N (age 79 years) there isnow the additional option to defer treatment.In each state we compare three possible actions:deferral, treatment and abandonment. If theaneurysm is 7 cm, deferral is calculated as theexpected net benefits from waiting another period(6 months), in which three possible states ofhealth could occur: no growth, growth by 0.5 cm(to 7.5 cm) or growth by 1 cm (to 8 cm). Theprobabilities of these outcomes were calculatedin Table 71 to be 0.31, 0.52 and 0.17 respectively.Delaying a decision might generate benefits butit also has costs. Delaying a decision might havevalue because it allows resolution of the uncertainty127© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidenceabout whether the aneurysm will grow, which inturn would change the treatment decision, withgreater benefit than either immediate treatmentor never offering surgery. If delay is permitted inperiod N, the optimal strategy in period N + 1 is nosurgery if the aneurysm does not grow, no surgeryif the aneurysm grows to 7.5 cm and EVAR if theaneurysm grows to 8 cm. There are three sourcesof opportunity cost of delaying the decision. First,patients may rupture while waiting. Second, thereis a time preference for current benefits and sofuture uncertain benefits are discounted. Third,there is a monetary cost of monitoring, which isassumed to be one outpatient visit with CT scancosting £191. These costs and benefits of delay areexpressed in the following formula:Present value at 7 cm in period N of future netbenefit of deferral = (1–Pr(rupture)) ×e –r/2 × (0.31 × 0 + 0.52 × 0 + 0.17 × 1366)–191 = 37where Pr(rupture) is the probability of rupture for apatient with a 7-cm aneurysm, e is the exponentialfunction and r is the discount rate (0.035 per year).This can be compared with the counterfactual,which is the present value of immediate electiveEVAR at 7 cm in the period N. This was calculatedusing the decision model for EVAR described inthe previous section. For convenience, this value isshown relative to a policy of no surgery, so that ‘notreatment’ is always shown with a value of zero. Ifsurgery has been carried out there is no monetarycost of continued surveillance, nor will the patientrupture from untreated aneurysm.Therefore, if the aneurysm is 7 cm at 79 yearsthe optimal decision is to continue waiting, asthe net benefits of waiting are greater than thoseof treatment. For aneurysms < 7 cm the optimaldecision is to discharge the patient, becauseat period N+1 it will never be cost-effective totreat, regardless of the aneurysm growth rate. Foraneurysms > 7 cm it is not cost-effective to wait andthe best strategy is immediate treatment.The same algorithm is used to calculate the netbenefits for each aneurysm size in period N–1,and the process continues by backward inductionuntil period 1 is reached. In most dynamicprogramming applications the main interest isin the decision at period 1 and the future periodcalculations are performed merely to inform thatdecision. 10 In this application, however, we are alsointerested in the grid of policies for all ages andaneurysm sizes, as this indicates the most costeffectivepolicy for any patient at diagnosis.Results of the comparison ofimmediate surgery, watchful waitingand no intervention strategiesResults of watchful waiting model forpatients of very poor operative fitnessTable 72 shows the optimum policy for patientsof very poor operative fitness at each age andaneurysm size, under base-case assumptions andat thresholds of £20,000 and £30,000 per QALY.Patients are similar to those who were eligible forthe EVAR trial 2. The results show that, for patientsof very poor fitness, EVAR might be cost-effective at£20,000 per QALY up to 77 years in patients withan aneurysm of 8 cm, up to 74 years in patientswith an aneurysm of 6 cm and up to 71.5 years inpatients with an aneurysm of 5 cm. Increasing thethreshold to £30,000 per QALY increases the age atwhich EVAR is cost-effective by about 2 years.The model predicts that watchful waiting would becost-effective for patients with a small aneurysm of4 cm up to age 68.5 years at a threshold of £20,000per QALY. For patients with a larger aneurysm,delaying treatment might be cost-effective forsome patients on the margin of the treat/dischargedecision. For patients with an aneurysm > 4 cm,waiting might be cost-effective for up to 18 months(three periods).Scenario 17 in Table 67 showed that if EVAR haslower costs and a lower rate of reinterventionthan in the base case, the ICER for EVAR versusopen repair for patients fit for open surgery wasapproximately £12,000 per QALY. We carriedout a further sensitivity analysis comparing EVARwith watchful waiting for patients who are not fitfor open surgery, that is, with a very poor risk ofoperative mortality, using the costs and rate ofreinterventions in scenario 17. The results areshown in Table 73. In this scenario the decisionabout whether to treat with EVAR or to offer notreatment is broadly similar to that in the base case.Results of watchful waiting model forpatients of poor operative fitnessThe previous analysis considered managementoptions for patients who might be considered forthe EVAR trial 2, that is, with very poor operativerisk under open surgery. It is also possible touse this model to examine management optionsfor patients who might be considered for EVARtrial 1, that is, when aneurysm repair might be128

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 72 Base-case results of the dynamic programme decision model for patients of very poor operative fitness, at thresholds of cost-effectiveness of £20,000 and £30,000 per QALYAge (years)68 69 70 71 72 73 74 75 76 77 78 79 80 81 82Aneurysm size(cm)Threshold of £20,000 per QALYSmall 4 W W W N N N N N N N N N N N N N N N N N N N N N N N N N N N N4.5 O O E E E E E W N N N N N N N N N N N N N N N N N N N N N N N5 E E E E E E E E E W W N N N N N N N N N N N N N N N N N N N NMedium 5.5 E E E E E E E E E E E E N N N N N N N N N N N N N N N N N N N6 E E E E E E E E E E E E E N N N N N N N N N N N N N N N N N NLarge 6.5 E E E E E E E E E E E E E E W W N N N N N N N N N N N N N N N7 E E E E E E E E E E E E E E E E E W W N N N N N N N N N N N NVery 7.5 E E E E E E E E E E E E E E E E E E E E N N N N N N N N N N Nlarge8 E E E E E E E E E E E E E E E E E E E E N N N N N N N N N N NThreshold of £30,000 per QALYSmall 4 W W W W W W W W N N N N N N N N N N N N N N N N N N N N N N N4.5 E E E E E E E E E E E W N N N N N N N N N N N N N N N N N N N5 E E E E E E E E E E E E E W W N N N N N N N N N N N N N N N NMedium 5.5 E E E E E E E E E E E E E E E W N N N N N N N N N N N N N N N6 E E E E E E E E E E E E E E E E E N N N N N N N N N N N N N NLarge 6.5 E E E E E E E E E E E E E E E E E E W W N N N N N N N N N N N7 E E E E E E E E E E E E E E E E E E E E E W W W N N N N N N NVery 7.5 E E E E E E E E E E E E E E E E E E E E E E E E N N N N N N Nlarge8 E E E E E E E E E E E E E E E E E E E E E E E E E N N N N N NE, EVAR; N, no surgical intervention; O, open repair; W, watchful waiting.129© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Assessment of cost-effectiveness evidence130TABLE 73 Sensitivity analysis: results of the dynamic programme decision model for patients of very poor operative fitness, at thresholds of cost-effectiveness of £20,000 and £30,000 per QALYAge (years)68 69 70 71 72 73 74 75 76 77 78 79 80 81 82Aneurysm size(cm)Threshold of £20,000 per QALYSmall 4 W W W W W N N N N N N N N N N N N N N N N N N N N N N N N N N4.5 E E E E E E E E E W N N N N N N N N N N N N N N N N N N N N N5 E E E E E E E E E E E W N N N N N N N N N N N N N N N N N N NMedium 5.5 E E E E E E E E E E E E E N N N N N N N N N N N N N N N N N N6 E E E E E E E E E E E E E E N N N N N N N N N N N N N N N N NLarge 6.5 E E E E E E E E E E E E E E E W W N N N N N N N N N N N N N N7 E E E E E E E E E E E E E E E E E E W W N N N N N N N N N N NVery 7.5 E E E E E E E E E E E E E E E E E E E E E N N N N N N N N N Nlarge8 E E E E E E E E E E E E E E E E E E E E E N N N N N N N N N NThreshold of £30,000 per QALYSmall 4 W W W W W W W W W N N N N N N N N N N N N N N N N N N N N N N4.5 E E E E E E E E E E E E W N N N N N N N N N N N N N N N N N N5 E E E E E E E E E E E E E E W N N N N N N N N N N N N N N N NMedium 5.5 E E E E E E E E E E E E E E E E W N N N N N N N N N N N N N N6 E E E E E E E E E E E E E E E E E E N N N N N N N N N N N N NLarge 6.5 E E E E E E E E E E E E E E E E E E W W W N N N N N N N N N N7 E E E E E E E E E E E E E E E E E E E E E E W W W N N N N N NVery 7.5 E E E E E E E E E E E E E E E E E E E E E E E E E N N N N N Nlarge8 E E E E E E E E E E E E E E E E E E E E E E E E E E N N N N NE, EVAR; N, no surgical intervention; W, watchful waiting.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48cost-effective compared with watchful waiting ordischarging the patient, taking account of age,fitness and aneurysm size.In this analysis we consider options for patientswho have poor operative fitness. Table 59 showedthat such patients aged 75 years with an aneurysmof 6.5 cm would have a probability of operativemortality with EVAR of 0.04 and with open repairof 0.12. This would put them on the marginsof eligibility for the EVAR trial 1 and EVARtrial 2. Current guidelines are unclear aboutthe management of these patients. All otherparameters are as in the base case.The results of the dynamic programme are shownin Table 74. At a threshold of £20,000 per QALY,EVAR would be cost-effective up to age 82.5 yearsfor an aneurysm of 8 cm and between 74 and 78years for an aneurysm of 6 cm. With base-caseassumptions, younger patients would be morecost-effectively treated with open repair, consistentwith Table 68. At £30,000 per QALY, EVAR wouldbe cost-effective up to 85 years for an aneurysm of8 cm and up to 80 years for an aneurysm of 6 cm.For patients with an aneurysm of 5 cm the modelpredicts that EVAR is cost-effective up to about78 years, with watchful waiting until 79 years.For patients with an aneurysm of 4 cm the modelpredicts that watchful waiting is cost-effective up to75.5 years if the aneurysm does not grow.DiscussionConventionally, patients have been classified asfit or unfit for open surgery, and AAA repair hasbeen offered to all patients fit for open surgerywith an aneurysm size of ≥ 5.5 cm. This chapterhas presented two models. The first examinedEVAR versus open repair in patients accordingto the conventional classification of fit for opensurgery and with large aneurysms of ≥ 5.5 cm. Thesecond explored the cost-effectiveness of differentpolicies concerning when, as well as how, surgeryshould be offered. In both models results havebeen presented by age, fitness and aneurysm sizeat diagnosis. Fitness in these models is defined ina general way so that a person of moderate fitnesswill have twice the operative mortality of a patientwith the same size of aneurysm and of the same agewith no pre-existing conditions.Summary of model results: patientsconsidered suitable for surgical repairThe base-case decision model found that EVARis not cost-effective on average for patients© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.who are fit for open surgery, with an ICER of£49,000 per QALY and decision uncertainty thatEVAR might be cost-effective of 0.42. However,these assumptions are based on historical data,particularly the EVAR trial 1. First, as EVAR hasbecome more widely used, it is plausible that thecosts of the EVAR procedure, particularly the timespent in the intensive care unit and operatingtheatre, have fallen faster than those of open repairsince the start of the decade. This hypothesis isdifficult to test using observational data becausethe case mix of patients undergoing EVAR mayalso have changed over this period. Second, it isplausible that the EVAR trial 1 overestimates therelative rate of reinterventions of EVAR versus openrepair because it does not include late laparotomiesand it is now less common to reoperate on sometypes of endoleak. Third, and related to theprevious point, the frequency and cost of routinesurveillance after EVAR may have been diminishingin recent years. Under this more favourablescenario, EVAR has an ICER of £12,000 per QALYand a probability of being cost-effective of 0.74versus open repair at a threshold of £20,000 perQALY.The model also considered how cost-effectivenessmight vary by subgroups defined by age, aneurysmsize and fitness. If patients can be classified intogood, average and poor operative risk, then forpatients of most ages and aneurysm sizes, EVARis cost-effective compared with open repair inpatients of poor risk but not cost-effective inpatients of good risk. The absolute benefit of EVARcompared with open repair is low in patients ofgood operative risk. Furthermore, there is a longtermrisk of complications and reinterventions afterEVAR. The decision is very uncertain in patients ofmoderate risk.Summary of model results: managementof patients with poor or very poor fitnessCurrent UK clinical practice is that electivesurgery is generally recommended for patientswith aneurysms of ≥ 5.5 cm or with aneurysms> 4.5 cm that have increased in diameter by morethan 0.5 cm in the last 6 months. However, theseguidelines are based on the risks and benefits ofopen surgery and do not take account of costs.Neither do they take account of the findings of theEVAR trial 2, which called into question whetheraneurysm repair was effective for unfit patients.The decision model has been used to identify thecost-effective management of patients for whomEVAR is an option, according to age and aneurysmsize.131

Assessment of cost-effectiveness evidence132TABLE 74 Results of the dynamic programme decision model for patients of poor operative fitness, at thresholds of cost-effectiveness of £20,000 and £30,000 per QALY, from 70 to 85 years of ageAge (years)70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85Aneurysm size(cm)Threshold of £20,000 per QALYSmall 4 W W W W W W W N N N N N N N N N N N N N N N N N N N N N N N N4.5 O O O O O O O O O O O O N N N N N N N N N N N N N N N N N N N5 O O O O O O O O O O O O O W W N N N N N N N N N N N N N N N NMedium 5.5 O O O O O O O O O O O O O O E E N N N N N N N N N N N N N N N6 O O O O O O O O E E E E E E E E E N N N N N N N N N N N N N NLarge 6.5 O O O O O O E E E E E E E E E E E E W W N N N N N N N N N N N7 E E E E E E E E E E E E E E E E E E E E E W W W N N N N N N NVery 7.5 E E E E E E E E E E E E E E E E E E E E E E E E W N N N N N Nlarge8 E E E E E E E E E E E E E E E E E E E E E E E E E E N N N N NThreshold of £30,000 per QALYSmall 4 O O W W W W W W W W W W N N N N N N N N N N N N N N N N N N N4.5 O O O O O O E E E E E E E E E W N N N N N N N N N N N N N N N5 O E E E E E E E E E E E E E E E E W W N N N N N N N N N N N NMedium 5.5 E E E E E E E E E E E E E E E E E E E E N N N N N N N N N N N6 E E E E E E E E E E E E E E E E E E E E E N N N N N N N N N NLarge 6.5 E E E E E E E E E E E E E E E E E E E E E E W W W N N N N N N7 E E E E E E E E E E E E E E E E E E E E E E E E E E W W W N NVery 7.5 E E E E E E E E E E E E E E E E E E E E E E E E E E E E E W Nlarge8 E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E EE, EVAR; N, no surgical intervention; O, open repair; W, watchful waiting.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48For patients who would be considered unsuitablefor open surgery according to current guidelines,that is, with very poor operative fitness, the modelpredicts that EVAR might be cost-effective at athreshold of £20,000 per QALY up to 77 years inpatients with an 8-cm aneurysm, up to 74 years inpatients with a 6-cm aneurysm and up to 71.5 yearsin patients with a 5-cm aneurysm. Increasing thethreshold to £30,000 per QALY increases the age atwhich EVAR is cost-effective by about 2 years.The model predicts that watchful waiting would becost-effective for patients with a small aneurysm of4 cm up to age 68.5 years at a threshold of £20,000per QALY. For patients with a larger aneurysm,delaying treatment might be cost-effective forsome patients on the margin of the treat/dischargedecision. For patients with an aneurysm > 4 cm,waiting might be cost-effective for up to 18 months(three periods). These results are fairly robust toassumptions about the cost of EVAR.The model was also used to explore managementoptions in patients with poor fitness. Such patientscould be considered on the margin of eligibilityfor EVAR trial 1. At a threshold of £20,000 perQALY, EVAR would be cost-effective up to age 82.5years for an aneurysm of 8 cm and between 74 and78 years for an aneurysm of 6 cm. With base-caseassumptions, younger patients would be morecost-effectively treated with open repair. However,these results are sensitive to model assumptions. Ata threshold of £30,000 per QALY, EVAR would becost-effective up to age 85 years for an aneurysm of8 cm and up to 80 years for an aneurysm of 6 cm.For patients with a small aneurysm at the uppermargin of fitness for open surgery the modelsuggests that current guidelines ought to bereassessed. The model predicts that watchfulwaiting is cost-effective for such patients with ananeurysm of 4 cm up to 75.5 years. For patientswith an aneurysm of 5 cm the model predicts thatEVAR is cost-effective at a threshold of £30,000 perQALY up to about 78 years, with watchful waitinguntil 79 years.The model including watchful waiting and notreatment is exploratory because it is based on dataon the natural history of AAAs rather than on acomparison between treatment and no treatmentin a controlled experimental setting such as anRCT. We can compare the results of EVAR trial 2with the model predictions. At up to 4 years followupthe EVAR trial 2 46 did not find any benefit forEVAR in the intention to treat analysis (primaryadjusted HR EVAR versus no intervention 1.00,© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.95% CI 0.54 to 1.84), with higher cost in the EVARgroup. The RCT authors concluded that EVARwas not effective or cost-effective for patients withvery poor fitness. Patients enrolled in EVAR trial2 46 had a mean age of 77 years and a mediananeurysm size of 6.4 cm (IQR 6–7.4 cm). Themodel broadly supports these conclusions, that is,for this ‘average’ patient, no intervention is costeffectiveat a threshold of £20,000 per QALY, andwatchful waiting is cost-effective at a threshold of£30,000 per QALY. A watchful waiting policy wasnot formally evaluated by the RCT. However, therewas a high proportion of crossovers in the trial –27% (47/172) of patients in the no interventionarm had an aneurysm repair by 4 years. 46 Thismight indicate a high degree of uncertainty aboutthe optimal management of these patients, suchthat many clinicians followed a ‘de facto’ watchfulwaiting policy despite the trial protocol. The trialwas not powered to formally undertake subgroupanalysis and therefore the model results cannot becompared to the RCT results for different ages andaneurysm sizes.Limitations of the model comparingEVAR and open repairThese conclusions are sensitive to the modelassumptions. We discuss the strengths andlimitations of the main assumptions in turn.First, the base case assumes that the treatmenteffect is proportional to operative risk, that is,the OR for EVAR versus open repair is constantfor all levels of fitness, aneurysm sizes and ages.This implies that the absolute difference betweenEVAR and open repair in the proportions who diewithin 30 days is low in patients at low operativerisk. There is some evidence that this assumptionis reasonable 23,96 (see Chapter 3). Brown et al. 23found no significant interaction between CPI riskscore and treatment effect for the patients in theEVAR trial 1. Schermerhorn et al. 96 also found fairlyconstant ORs across all age ranges, and thereforethe absolute risk reduction (the difference in theoperative mortality rate between similar patients)increased with age. Although this comparisonused unrandomised data from Medicare, theauthors used propensity score matching tocompare treatment effects across a much moreheterogeneous set of patients than are usuallyentered in a clinical trial, and in a much largersample (almost 23,000 patients).Second, the base case assumes that the initialadvantage of EVAR compared with open repair isnot sustained in the medium term. For patientsat low and moderate risk, with a modest initial133

Assessment of cost-effectiveness evidence134difference in operative mortality, the survival curvesare predicted to meet between 1 and 3 years afterthe procedure. This assumption is supported by theresults of the EVAR trial 1, 43 the DREAM trial 40 andSchermerhorn et al. 96Third, the base-case model assumed that lateaneurysm mortality after EVAR would be low,around 0.3% per year in patients with an aneurysmof 5–5.4 cm but constant over a patient’s lifetime.The most recent generations of devices requirelonger follow-up to confirm these results. The basecasemodel also predicted, from survival analysis ofthe EUROSTAR data, that late aneurysm mortalityafter EVAR in patients with a large aneurysm(≥ 6.5 cm) was considerably and significantly greaterthan that in patients with a small aneurysm (Table62; HR 3.75, SE 0.83), confirming earlier workon this data set. 82 However, patient selection intoEUROSTAR may limit its generalisability. AAAdiameter is a major determinant of the decisionabout surgery and is also an independent predictorof suitability for EVAR so that any results forpatients with large AAAs treated by EVAR are likelyto be based on a highly selective sample of patients.Therefore, this result requires further investigation.Fourth, the base case estimated the use of hospitalresources from the EVAR trial 1, as this was recentrandomised data relevant to the UK. Other nonrandomiseddata, 128,166,167 and the survey results inAppendix 3, have suggested that some elementsof the hospital costs of EVAR procedures, such aslength of stay in the intensive care unit, may havefallen more rapidly than the costs of open repairsince 2003. As discussed in Chapter 1, there isconsiderable variation in the prices paid for theendovascular stent and accessories. 166Fifth, the base case estimated the baseline rateof operative mortality after EVAR conditionalon fitness, aneurysm size and age from theEUROSTAR registry, 54 and estimated the rateafter open repair using the average OR from ameta-analysis of RCTs (Chapter 3). On averagein this population, the predicted rate of operativemortality after open repair in the model (5.7%) ishigher than that found by the DREAM and EVARtrial 1 (4.6% 40 and 4.2%, 23 respectively), but similarto that in the UKSAT trial (5.8% 158 ) in a youngerpatient group with smaller aneurysms and lowerthan that in the NVD registry (6.8%). It may bethat the EVAR and DREAM trials operated on amore selected patient group, or in more specialistcentres, than UKSAT. The base-case analysisassumes that the rates of operative mortality in themodel are achievable on average in the UK.Finally, throughout this analysis, fitness hasreferred to the risk of operative mortality relativeto a patient of that age and aneurysm size with nocomorbidities. Although fitness is an importantfactor in the analysis, there is currently novalidated risk score system to quantify this riskboth for EVAR and for open surgery. This makes itdifficult to translate the findings presented in thisanalysis into recommendations for clinical practice.The development of a recognised risk scoringinstrument for operative mortality that is valid forEVAR and open surgery is a matter of urgency. 142Despite the lack of such an instrument there isconsiderable evidence that clinicians are skilledat identifying patients of lower than average,average and higher than average risk of operativemortality, 23,65 taking account of a range offactors including cardiac conditions, pulmonarydisorders, malignant disease, obesity and previouslaparotomy. Indeed, this subjective assessmentis a component of the current guideline used todetermine whether a patient is suitable for surgicalrepair and to obtain informed consent. Thedefinition of ‘good’ fitness used in this analysis issimply the absence of any of these comorbidities,and it would therefore be straightforward tomeasure in individual patients. The results of thisanalysis suggest that EVAR is unlikely to be costeffectivein this good fitness group in any of thescenarios evaluated (Table 68).Limitations of the model comparingsurgery with watchful waitingThe watchful waiting model has two submodels:a model comparing EVAR with open repair, toestimate outcomes with surgery, and a modelcalculating the natural history of untreatedaneurysm, to estimate QALYs without any surgicalintervention. Therefore, all of the limitations listedabove apply to the watchful waiting model. Below,we discuss the additional assumptions required bythe natural history model.The parameters comparing the relative risksof operative mortality, reinterventions and latemortality after open surgery and EVAR wereobtained from recent RCTs. 40,43 However, themodel comparing surgery with watchful waitingdid not use treatment effects from RCTs. This isbecause the crossovers, delays and absence of awatchful waiting protocol in EVAR trial 2 46 makethe results difficult to use directly to identify themost cost-effective form of management. Althoughthe UKSAT trial 158 did have a clear policy forinterventions, it did not evaluate EVAR. Therefore,we could not use treatment effects from these two

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48RCTs to inform the model. Instead, the naturalhistory of patients with untreated aneurysm wasestimated using rupture rates and growth ratesobtained from a review of the literature, andcompared with outcomes estimated by the model ofEVAR and open repair for patients with the samebaseline characteristics.Given the uncertainties in the data, and thepotential for bias in this non-randomisedcomparison, the decision model and dynamicprogramme for watchful waiting are intended to beexploratory. Nevertheless, as discussed above, theresults appear broadly consistent with those of theEVAR trial 2, if it is accepted that the crossoversand delays for surgery represent a ‘de facto’watchful waiting strategy by the trial participants. Itwould be difficult to design an RCT that was able tocompare all of the policies considered in this modeland to stratify results by patient characteristics.Therefore, more precise data are needed fromclinical studies of rupture rates and growth ratesof untreated aneurysm and the risk factors forrupture. There is some evidence that rupture ratestend to be greater in women for a given aneurysmsize. 154 The optimal treatment policy for womenhas not been fully addressed in this analysis andrequires further work.In the absence of information about theeffectiveness of policies to improve fitness, it isassumed constant (relative to the patient’s ageand aneurysm size) over the patient’s lifetime.In effect, elective operative mortality worsensbecause of advancing age and aneurysm growthin these analyses. It may be that fitness can beimproved in some patients. 142 The UKSAT trial 158concluded that one reason for the slightly betterlong-term outcomes after early surgery comparedwith delayed surgery might be that patients weremore likely to give up smoking after surgery. Theeffectiveness of policies with the aim of improvingfitness should be a matter for urgent research.Management of patients withsmall aneurysms with EVARThe guideline that aneurysm repair should not beundertaken in patients with an aneurysm size of< 5.5 cm is based on the UKSAT trial. 158 However,this RCT did not include EVAR, nor do theguidelines consider costs. Our decision analysissuggests that the cost-effectiveness of managementstrategies is sensitive to model assumptions andpatient characteristics of age and aneurysm size.There is, therefore, continuing uncertainty aboutthe cost-effectiveness of EVAR in patients withsmall aneurysms. The ongoing CAESAR trial, 52comparing EVAR and surveillance, will providesome evidence relating to this patient group.ConclusionsThe main conclusions of the decision analysis are:• EVAR is not cost-effective compared with openrepair on average given base-case assumptionsat a threshold of £30,000 per QALY.• The results are very sensitive to modelassumptions. EVAR may be more costeffectivethan open repair if the relative costsof the procedure are less, reinterventionsare relatively less frequent and follow-upsurveillance is currently less intensive than inthe base-case assumptions.• The results are sensitive to the baseline riskof operative mortality, with EVAR appearingto be most cost-effective compared with openrepair in the least fit patients. A validated andaccepted fitness score is needed.• In patients considered to be of very poorfitness (unfit for open repair according tocurrent guidelines), EVAR may be cost-effectiveat a threshold of £20,000 per QALY up to 77years in patients with an 8-cm aneurysm, upto 74 years in patients with a 6-cm aneurysmand up to 71.5 years in patients with a 5-cmaneurysm. Increasing the threshold to £30,000per QALY increases the age at which EVAR iscost-effective by about 2 years. The modellingof EVAR versus no intervention and watchfulwaiting is indicative and exploratory, basedon assumptions about the natural history ofuntreated aneurysm in patients anatomicallysuitable for EVAR. Further research in theseareas would be important to inform futuremodelling work.• Indicative modelling results suggest that EVARmay be cost-effective in some patient groupsfor small aneurysms and the current guidelinethat aneurysm should not be treated in patientswith an aneurysm of < 5.5 cm should bereviewed.135© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 5Assessment of factors relevant tothe NHS and other partiesEndovascular repair for AAA is already awell-established and widely used technologythroughout the NHS. It is, however, a difficulttechnology to research and hence the evidencebase leaves many questions regarding best practiceunresolved. This is a rapidly evolving technology,with improved and more specific devices beingdeveloped, and the range of patients eligiblefor EVAR is likely to expand as the technologydevelops. Furthermore, ongoing research into thenatural history of AAA will further inform clinicalpractice. Thus, the treatment protocols relating toAAA and EVAR will continue to evolve.The National Screening Committee for theUK (March 2007) has recommended that AAAscreening be offered to men aged 65 years,provided that the men invited are given clearinformation about the risks of elective surgery.Screening will lead to an increase in the numberof AAA cases being identified for treatment,particularly small aneurysms. Steps will need tobe taken to create networks of vascular surgicalservices to allow further specialisation and abigger throughput of cases. Provided adequateresources and training are available, the increasedvolume should reduce the risk of surgery (open orEVAR) as there is evidence correlating volume andquality. 168It is necessary, as with any treatment decision, toconsider ethical issues when choosing between AAAprocedures. EVAR has significantly improved the30-day mortality rate compared with open repairand has an equivalent medium-term all-causedeath rate. When deciding on the best treatmentfor a patient an individual surgeon may decide thatthe short-term gains of EVAR outweigh the lack ofa long-term advantage.Irrespective of the potential benefits of EVAR, asignificant proportion of all AAA patients (55% inan unselected series 13 ) are unsuited to EVAR onthe grounds of anatomy. Even with developmentsin EVAR device design it is unlikely that therequirement for open repair will diminish in thenear future. It is therefore essential that the NHSmaintains provision of, and continues to developexpertise in, open repair.137© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 6DiscussionStatement of principalfindingsCurrently, EVAR trial 1, 42,43 EVAR trial 2 46 and theDREAM trial 40,41 represent the best randomisedevidence for evaluating EVAR. In patients fit forboth procedures EVAR reduces operative mortalitycompared with open repair and is associatedwith a reduction in aneurysm-related mortalityover the medium term but there is no significantdifference in all-cause mortality between EVARand open repair at mid-term follow-up. The lackof a long-term mortality benefit with EVAR iscompounded by an increased rate of complicationsand reinterventions and these are not offset byany increase in HRQoL, possibly because of theincreased level of monitoring required with EVARbecause of the risk of complications.There is limited RCT evidence comparing EVARwith non-surgical management in patients unfit foropen repair. EVAR trial 2 46 found no differences inmortality outcomes between groups but this findingcannot be taken as definitive because substantialnumbers of patients randomised to non-surgicalmanagement crossed over to receive surgical repairof their aneurysms. This may indicate that thebenefits of EVAR over ‘watchful waiting’ may onlybe apparent in the very long term.The results from these trials are complemented bydata from registries, in particular the EUROSTARregistry data relating to devices in current use. 54Although not formally part of our review, thefindings of the very large observational studyrecently published by Schermerhorn et al. 96 reflectthose of the RCTs. Importantly, this study suggeststhat, although across all age groups the initialbenefit of EVAR over open repair diminishesover time, the rate of conversion between the twotreatments is slower in older patients. This suggeststhat less fit patients may benefit from EVAR morethan fit patients.Very few data on the use of EVAR for rupturedaneurysms are available and, as yet, it is unclearwhether EVAR is an appropriate or beneficialintervention in this indication. An ongoing© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.study 48 should contribute data to help inform thisquestion.The base-case decision models developed by theYork assessment team found that EVAR is unlikelyto be cost-effective compared with open repairon average. For patients of poor or very poorfitness, the base-case model found that EVAR ismore cost-effective than open repair. This result issensitive to model assumptions and EVAR may bemore cost-effective than open repair under otherplausible assumptions, particularly about costs andreinterventions.In patients with very poor fitness EVAR should becompared with options of no surgery or delayedsurgery. In patients unfit for open repair andeligible for EVAR trial 2, with an aneurysm of6.5 cm and aged 77 years, the model suggests thatno intervention is cost-effective at a threshold of£20,000 per QALY, and watchful waiting is costeffectiveat a threshold of £30,000 per QALY. Theseresults appear broadly consistent with the resultsof the EVAR trial 2. The model suggests that EVARmay be cost-effective at £20,000 per QALY up to77 years in patients with an 8-cm aneurysm, up to74 years in patients with a 6-cm aneurysm and upto 71.5 years in patients with a 5-cm aneurysm.Increasing the threshold to £30,000 per QALYincreases the age at which EVAR is cost-effectiveby about 2 years. This modelling work is based onunrandomised comparisons and is intended to beexploratory.Strengths and limitationsof the assessmentThis review of the evidence used establishedsystematic review methods. 37 We defined inclusionand exclusion criteria in advance. We applied arigorous search strategy to a range of electronicand print sources. We also ensured that the reviewwas kept up to date by using a current awarenessstrategy. Finally, we quality assessed RCTs beforeperforming a meta-analysis when possible andappropriate. A more definitive analysis would bean individual patient data analysis of all completedand currently ongoing trials of EVAR.139

Discussion140We attempted to obtain any extra trial data onEVAR for unruptured aneurysms above that used ina previous systematic review of the RCT literature. 35Data from EVAR trial 1 and EVAR trial 2 weresupplied on an academic-in-confidence basis.Additional analyses of data from the EVAR trialshave been published and were also included in thereview as appropriate. Our synthesis of the RCTdata differs slightly from that of Lederle et al. 35 inthat they used ORs whereas we used HRs in ourmeta-analysis to provide a more precise measure ofeffect. However, this did not affect the findings ofthe meta-analysis.The best RCTs in the review included patients withaneurysms of at least 5.5 cm in diameter. Ongoingtrials that have included patients with aneurysms of5 cm will contribute to the general evidence base ofEVAR versus open repair but will also specificallyinform the debate about the lower aneurysm sizelimit that can be treated beneficially with EVAR. 49,50This review found a limited number of RCTs,particularly for patients unfit for open repair andfor those with ruptured aneurysms. The lack ofRCTs limits the strength of the conclusions thatmay be drawn. In addition, the data from boththe RCTs and the registries are derived almostentirely from male patients. Although a veryhigh proportion of the patients in the studies isrepresentative of patients who develop AAA, theestimates of clinical effect will reflect the treatmentof male patients more than female patients.The registries included in the review were selectedbased on perceived relevance to the reviewquestion. The main strength of registry data isthat they may give an indication of outcomesachieved in routine clinical practice. However,it should be noted that some data are old andthus may not reflect current practice. This isparticularly the case for the RETA registry, 56which stopped adding new cases in 2000 whenthe EVAR trial 1 and EVAR trial 2 studies began.The EUROSTAR registry 54 provides data on alarge sample of patients undergoing EVAR, withmost data being recorded prospectively. Althoughprobably the strongest source of registry data onEVAR, a possible limitation of EUROSTAR is thatit includes relatively few centres from the UK andmay not entirely reflect UK practice. The UKNVD 16 currently concentrates on open repair ofAAAs almost exclusively and therefore (becausepatients are not routinely followed up after openrepair) includes only short-term outcomes (i.e. 30-day mortality) in its published reports.The studies on risk models provide pointers forfurther research and show decision-makers wheredata are limited, contradictory or uncertain. Themajority of studies assess relationships betweenpreoperative risk factors and patient outcomesfollowing EVAR. We have provided a narrativeand graphical synthesis of these studies and thisillustrates which factors have generally beenfound to be significant independent risk factors inmultivariate analyses. We are conscious, however,of potential reporting bias as factors not foundto be significant in analyses may not always havebeen reported in the included studies. Thereforewe have been cautious in our summary statements,indicating which may be significant risk factorsoverall. In addition, there is inconsistency inthe combinations of factors used in multivariatemodels and this supports the decision to usebroad categories of patient fitness rather thanany specific risk scoring system in the economicmodel included in this report (see Chapter 4, Yorkeconomic assessment).A further limitation of most of the includedrisk modelling studies is that methodologywas poorly reported. This, together with a lackof validated quality assessment tools for suchstudies, makes it difficult to stratify the studies interms of quality. We have focused on the studiesthat evaluated existing risk algorithms 23,59,86 andthe one study that developed a risk algorithmfrom scratch 21,60,92 because these appear to bepotentially the most useful for clinical decisionmaking.Further research is required to developtools to compare possible outcomes of EVAR andalternative strategies (open repair and non-surgicalmanagement with or without later surgery).The modelling undertaken by the York assessmentteam builds on earlier work undertaken by a subsetof authors. In general, a strength of the modellingis that it uses both RCT and registry data in anattempt to identify the most cost-effective formof management for each type of patient (in whichfitness, age and aneurysm diameter are the keyvariables characterising patients). This approachhighlights the heterogeneity in cost-effectivenessin this area and suggests that it may not beappropriate to define one form of management asthe most cost-effective in all types of patients. Themodelling approach has also sought to handle theissue of appropriate comparators by presenting twomodels. The first model assumes (as was the casein EVAR trial 1) that a decision has been taken tooperate on a patient and the question is whetherEVAR or open surgery should be provided. Thesecond model widens the comparators by including

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48two additional strategies: watchful waiting and thedecision not to intervene.All models in this area are subject to uncertaintyin the assumptions made and the evidence used.These have been dealt with using appropriatesensitivity and scenario analyses. Differentperspectives on structural assumptions and choiceof evidence also largely explain differences betweenthe York model, those in the published literatureand that submitted to NICE by Medtronic. Theseuncertainties are considered in the followingsection.UncertaintiesIn general, the main uncertainties that mayinfluence this assessment are:• the uncertainty regarding the natural history ofAAA if left untreated• the uncertainty regarding the effect size ofEVAR in smaller aneurysms; this questionis currently being addressed in two ongoingtrials, ACE and OVER (see Chapter 3, OngoingRCTs)• the uncertainty regarding the effect size ofEVAR compared with watchful waiting• the uncertainty regarding the impact of variouslevels of risk on the outcome following EVAR.For the economic modelling in particular there aresome specific uncertainties about assumptions anddata sources:• The base case assumes that the treatmenteffect is proportional to operative risk, thatis, the odds ratio for EVAR versus open repairis constant for all levels of fitness, aneurysmsizes and ages. This implies that the absolutedifference between EVAR and open repair inthe proportion who die within 30 days is lowin patients at low operative risk. There is someevidence that this assumption is reasonable 23,96(see Chapter 5).• The base case assumes that the initialadvantage for EVAR compared with openrepair is not sustained in the medium term.For patients at low and moderate risk, with amodest initial difference in operative mortality,the survival curves are predicted to meetbetween 1 and 3 years after the procedure.This assumption is supported by the resultsof EVAR trial 1, 43 the DREAM trial 40 andSchermerhorn et al. 96 ••••The base-case model assumes that lateaneurysm mortality after EVAR would below, around 0.3% per year in patients withan aneurysm of 5–5.4 cm, but constant overa patient’s lifetime. It also predicted, fromsurvival analysis of the EUROSTAR data,that late aneurysm mortality after EVAR inpatients with a large aneurysm (≥ 6.5 cm) wasconsiderably and significantly greater than thatin patients with a small aneurysm, confirmingearlier work on this data set. 82 However,patient selection into EUROSTAR may limitits generalisability. AAA diameter is a majordeterminant of the decision about surgery andis also an independent predictor of suitabilityfor EVAR and so any results for patients withlarge AAA treated by EVAR are likely to bebased on a highly selective sample of patients.The base case estimated the use of hospitalresources from EVAR trial 1 as this was recentrandomised data relevant to the UK. Othernon-randomised data 127,166,167 have suggestedthat the hospital costs of EVAR procedures mayhave fallen more rapidly than the costs of openrepair since 2003, although, as discussed inChapter 1, there is also considerable variationin the prices paid for the endovascular stentand accessories. 166The base case estimated the baseline rate ofoperative mortality after EVAR conditionalon fitness, aneurysm size and age from theEUROSTAR registry, 54 and estimated the rateafter open repair using the average odds ratiofrom a meta-analysis of RCTs. The predictedrate of operative mortality after open repair(5.7%) is greater than that found by theDREAM trial and EVAR trial 1 (4.6% 40 and4.2%, 23 respectively), and similar to that foundin the UKSAT trial in a younger patient groupwith smaller aneurysms (5.8% 158 ). It may bethat the EVAR and DREAM trials operatedon a more selected patient group, or in morespecialist centres, than UKSAT. The base-caseanalysis assumes that the rates of operativemortality in the model are achievable onaverage in the UK.Throughout this analysis, fitness has referredto the risk of operative mortality relative to apatient of that age and aneurysm size with nocomorbidities. This has been done because,although fitness is an important considerationin the management of patients, there is novalidated risk scoring system to quantify thisrisk both for EVAR and for open surgery.It may be that fitness can be improved insome patients, but there has been very little141© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Discussionevaluation to date of policies having thisobjective.• The model comparing surgery with watchfulwaiting did not use treatment effects fromRCTs. This is because the crossovers, delaysand absence of a watchful waiting protocol inEVAR trial 2 46 make the results difficult to usedirectly to identify the most cost-effective formof management. Although the UKSAT trial 158did have a clear policy for interventions, itdid not evaluate EVAR. Therefore, we couldnot use treatment effects from these two RCTsto inform the model. Instead, the naturalhistory of patients with untreated aneurysmwas estimated using rupture rates and growthrates obtained from a review of the literature,and compared with outcomes estimated by themodel of EVAR and open repair for patientswith the same baseline characteristics. Giventhe uncertainties in the data, and the potentialfor bias in this non-randomised comparison,the decision model and dynamic programmefor watchful waiting are intended to beexploratory.• As noted in Chapters 3 and 4, the RCT data onEVAR were predominantly collected in men.Although Chapter 3 reported that there was noevidence that either baseline risks or treatmenteffects were influenced by gender, it is feasiblethat untreated rupture rates may differ betweenmen and women, and this may influence thecost-effectiveness of the management options.142

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Chapter 7Conclusions• Compared with open repair EVAR reducesoperative mortality and aneurysm-relatedmortality over the medium term but offers nosignificant difference in all-cause mortality atmid-term follow-up.• EVAR is associated with an increased rate ofcomplications and reinterventions and theseare not offset by any increase in HRQoL.• Analysis of the EVAR trial data did not findany evidence that a benefit of EVAR over openrepair could be predicted using the CPI scorefor preoperative fitness.• There is evidence from single studies that theGAS and CCI scores can independently predictin-hospital or 30-day mortality after EVAR.The GAS may also be able to predict longertermmortality following EVAR.• A large number of studies have modelled risksfor adverse outcomes following EVAR. Thesedo not provide definitive evidence but age,possibly gender, renal impairment, fitness, ASAclass and aneurysm size may be predictive ofpoorer 30-day survival. There may be a linkbetween fitness for open repair, aneurysm sizeand possibly device type and aneurysm-relatedmortality. In terms of all-cause mortality,pulmonary status, renal impairment, ASA classand aneurysm size might adversely affect thisoutcome. We did not consistently find any riskfactors for reintervention. For the outcome ofendoleak, only age was a possible independentrisk factor.• There is limited RCT evidence comparingEVAR with non-surgical management orwatchful waiting in patients unfit for openrepair. The EVAR trial 2 found no differencesin mortality outcomes between groups but thisfinding cannot be taken as definitive.• There is no high-quality evidence for theefficacy of EVAR in the treatment of rupturedaneurysms.• EVAR is not cost-effective compared with openrepair on average using base-case assumptions.• The results are very sensitive to modelassumptions. EVAR may be cost-effectiveon average under alternative reasonablescenarios of how hospital costs and rates ofreintervention have changed in recent years.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.• In subgroup analysis, EVAR is likely to becost-effective in patients with a poor risk ofoperative mortality. EVAR is unlikely to becost-effective compared with open repair inpatients of good fitness, that is, in the absenceof comorbidity.• In an exploratory analysis of the managementof patients considered of very poor fitnessor unfit for open repair, EVAR may be costeffectiveat a threshold of £20,000 per QALYup to 77 years in patients with an 8-cmaneurysm, up to 74 years in patients with a6-cm aneurysm and up to 71.5 years in patientswith a 5-cm aneurysm. Increasing the thresholdto £30,000 per QALY increases the age atwhich EVAR is cost-effective by about 2 years.• The results are sensitive to assumptions anddata about the risk of late aneurysm death,reinterventions and the hospital cost of theprocedures. The modelling of no interventionand watchful waiting is indicative andexploratory, based on assumptions aboutthe natural history of untreated aneurysmin patients anatomically suitable for EVAR.Further research in all of these areas would beimportant to inform future modelling work.Implications for serviceprovision• Based on the results of this assessment ofclinical effectiveness and cost-effectiveness,open repair should be the treatment of choicefor patients with AAA who have good ormoderate fitness.• For patients with poorer fitness, whethersuitable for open repair or not, EVAR maybe cost-effective but this will depend upon apatient’s age.• EVAR cannot currently be recommended forthe treatment of ruptured aneurysms.Suggested research priorities• Further follow-up of the existing UK trials(EVAR trial 1, EVAR trial 2) should beundertaken.143

Conclusions• Opportunities for individual patient metaanalysisof all RCTs relating to EVAR should besought.• Further research is needed on the rate of lateaneurysm-related mortality after EVAR, inparticular for the most recent generations ofdevices.• The extent to which the relative treatmenteffect of EVAR on operative mortality can beassumed constant across subgroups of patientsshould be further investigated.• Research is required into how to implementthe best available risk scoring systems for themanagement of AAA into decision-making inroutine clinical practice.• Research is required into the natural historyof untreated AAA to determine more reliablywhen surgical intervention is optimal. Theanalysis should investigate the impact ofdifferent levels and determinants of patientfitness as well as aneurysm size and anatomy.• A well-defined and well-conducted RCT ofEVAR versus watchful waiting reflecting currentclinical practice is warranted. However, giventhe difficulties of conducting RCTs in themanagement of AAA, it is probably advisablethat the collection of data through the existing,established registries in the UK, particularlyRETA (for EVAR) and NVD (for open repair),should be continued.144

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48AcknowledgementsWe are grateful to Cheryl Craigs for assistancewith protocol development and studyselection; Christian Stock for assistance with thesummary figures for the risk modelling studies;Dr Jaap Buth (EUROSTAR) for giving us accessto raw data from the registry; Dr Buth and theinvestigators of the ACE, Amsterdam AcuteAneurysm Trial, OVER, NExT ERA and CAESARstudies for their responses to our requests forinformation; and the EVAR trial investigators forproviding unpublished data on an academic-inconfidencebasis.The views expressed in this report are those of theauthors and not necessarily those of the NIHRHTA Programme. Any errors are the responsibilityof the authors.Contributions of authorsDuncan Chambers (Research Fellow) wasinvolved in all stages of the clinical review, fromdevelopment of the protocol, through screeningstudies and data extraction to analysis andsynthesis and production of the final report. DavidEpstein (Research Fellow) was involved in all stagesof the review, design and analysis of the economicmodel and production of the final report. SimonWalker (Research Fellow) was involved in the costeffectivenesssection, study selection, developmentof the economic model and report writing. DebraFayter (Research Fellow) was involved in all stagesof the review, from development of the protocol,through screening studies and data extraction toanalysis and synthesis and production of the finalreport. Fiona Paton (Research Fellow) providedinput for the design and implementation ofdata extraction, analysed the registry data andcontributed to the final report. Kath Wright(Information Officer) devised the search strategy,carried out the literature searches and wrotethe search methodology sections of the report.Jonathan Michaels (Professor of Vascular Surgery)provided input at all stages of the review, assistedin the development of the model structure for theeconomic modelling and the natural history ofaortic aneurysm and commented on the results anddraft report. Stephen Thomas (Senior Lecturer andConsultant Vascular Radiologist) provided input atall stages of the review, assisted in the developmentof the model structure for the economic modellingand the natural history of aortic aneurysm andcommented on the results and draft report. MarkSculpher (Professor of Health Economics) providedinput at all stages of the review, commented ondrafts of the report and took overall responsibilityfor the economics section. Nerys Woolacott (SeniorResearch Fellow) provided input at all stages of thereview, commented on drafts of the report and tookoverall responsibility for the review.145© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48References1. Powell JT, Greenhalgh RM. Clinical practice.Small abdominal aortic aneurysms. N Engl J Med2003;348:1895–901.2. Brown LC, Powell JT. Risk factors for aneurysmrupture in patients kept under ultrasoundsurveillance. UK Small Aneurysm Trial Participants.Ann Surg 1999;230:289–96.3. Wilmink AB, Quick CR. Epidemiology andpotential for prevention of abdominal aorticaneurysm. Br J Surg 1998;85:155–62.4. Multicentre Aneurysm Screening Study Group. TheMulticentre Aneurysm Screening Study (MASS) intothe effect of abdominal aortic aneurysm screeningon mortality in men: a randomised controlled trial.Lancet 2002;360:1531–9.5. Multicentre Aneurysm Screening Study Group.Multicentre aneurysm screening study (MASS): costeffectiveness analysis of screening for abdominalaortic aneurysms based on four year results fromrandomised controlled trial. BMJ 2002;325:1135.6. National Institute for Health and ClinicalExcellence. Laparoscopic repair of abdominal aorticaneurysm. Report No. 229. London: NICE; August2007.7. United Kingdom Small Aneurysm Trial Participants.Long-term outcomes of immediate repair comparedwith surveillance of small abdominal aorticaneurysms. N Engl J Med 2002;346:1445–52.8. Lederle F, Wilson S, Johnson G. Immediate repaircompared with surveillance of small abdominalaortic aneurysms N Engl J Med 2002;346:1437–44.9. Brown LC, Epstein D, Manca A, Beard JD, PowellJT, Greenhalgh RM. The UK EndovascularAneurysm Repair (EVAR) trials: design,methodology and progress. Eur J Vasc Endovasc Surg2004;27:372–81.10. Driffield T, Smith P. A real options approach towatchful waiting: theory and an illustration. MedDecis Making 2007;27:178–88.11. Michaels J. The management of small abdominalaortic aneurysms: a computer simulation usingMonte Carlo methods. Eur J Vasc Surg 1992;6:551–7.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.12. National Institute for Health and ClinicalExcellence. Stent-graft placement in abdominal aorticaneurysm. Interventional Procedure Guidance 163.London: NICE; 2006.13. Woodburn KR, Chant H, Davies JN, Blanshard KS,Travis SJ. Suitability for endovascular aneurysmrepair in an unselected population. Br J Surg2001;88:77–81.14. Medicare Services Advisory Committee. Endoluminalgrafting for abdominal aortic aneurysm. Canberra:Medicare Services Advisory Committee; 1999.15. National Institute for Clinical Excellence. Guide tothe methods of technology appraisal. London: NICE;2004.16. Ashley S, Ridler B, Baker S, Kinsman R, PrytherchD, Vascular Society of Great Britain and Ireland.Fourth National Vascular Database report 2004. Henleyon-Thames:Dendrite Clinical Systems; 2005.17. Boyd O, Jackson N. Clinical review: how is riskdefined in high-risk surgical patient management?Crit Care 2005;9:390–6.18. Conners MS, III, Tonnessen BH, Sternbergh WC,III, Carter G, Yoselevitz M, Money SR. Does ASAclassification impact success rates of endovascularaneurysm repairs? Ann Vasc Surg 2002;16:550–5.19. Sutton R, Sarin S. Comparative surgical audit. InTaylor I, Johnson C, editors. Recent advances insurgery 26. London: Royal Society of Medicine Press;2003. pp. 201–13.20. Hadjianastassiou VG, Tekkis PP, Athanasiou T,Muktadir A, Young JD, Hands LJ. Comparison ofmortality prediction models after open abdominalaortic aneurysm repair. Eur J Vasc Endovasc Surg2007;33:536–43.21. Barnes M, Boult M, Maddern G, Fitridge R. Amodel to predict outcomes for endovascularaneurysm repair using preoperative variables. Eur JVasc Endovasc Surg 2008;35:571–9.22. Kertai MD, Boersma E, Klein J, van SambeekM, Schouten O, van Urk H, et al. Optimizingthe prediction of perioperative mortality invascular surgery by using a customized probabilitymodel [erratum appears in Arch Intern Med2005;165:1540]. Arch Intern Med 2005;165:898–904.147

References14823. Brown LC, Greenhalgh RM, Howell S, Powell JT,Thompson SG. Patient fitness and survival afterabdominal aortic aneurysm repair in patients fromthe UK EVAR trials. Br J Surg 2007;94:709–16.24. Dueck AD, Kucey DS, Johnston KW, Alter D,Laupacis A. Survival after ruptured abdominalaortic aneurysm: effect of patient, surgeon, andhospital factors. J Vasc Surg 2004;39:1253–60.25. Faizer R, DeRose G, Lawlor DK, Harris KA, ForbesTL. Objective scoring systems of medical risk:a clinical tool for selecting patients for open orendovascular abdominal aortic aneurysm repair. JVasc Surg 2007;45:1102–8.26. Baas A, Janssen K, Prinssen M, Buskens E,Blankensteijn J. The Glasgow Aneurysm Scoreas a tool to predict 30-day and 2-year mortalityin the patients from the Dutch RandomizedEndovascular Aneurysm Management trial. J VascSurg 2008;47:277–81.27. Hirzalla O, Emous M, Ubbink DT, Legemate D.External validation of the Glasgow Aneurysm Scoreto predict outcome in elective open abdominalaortic aneurysm repair. J Vasc Surg 2006;44:712–16.28. Gilbert K, Larocque B, Patrick L. Prospectiveevaluation of cardiac risk indices for patientsundergoing noncardiac surgery. Ann Intern Med2000;133:356–9.29. Sharif MA, Lee B, Makar RR, Loan W, Soong CV.Role of the Hardman index in predicting mortalityfor open and endovascular repair of rupturedabdominal aortic aneurysm. J Endovasc Ther2007;14:528–35.30. Nesi F, Leo E, Biancari F, Bartolucci R, RainioP, Satta J, et al. Preoperative risk stratification inpatients undergoing elective infrarenal aorticaneurysm surgery: evaluation of five risk scoringmethods. Eur J Vasc Endovasc Surg 2004;28:52–8.31. Tang T, Walsh S, Prytherch D, Wijewardena C,Gaunt M, Varty K, et al. POSSUM models in openabdominal aortic aneurysm surgery. Eur J VascEndovasc Surg 2007;34:499–504.32. Tambyraja A, Lee A, Murie J, Chalmers R.Prognostic scoring in ruptured abdominal aorticaneurysm: a prospective evaluation. J Vasc Surg2008;47:282–6.33. Tang T, Walsh SR, Prytherch DR, Lees T, Varty K,Boyle JR. VBHOM, a data economic model forpredicting the outcome after open abdominal aorticaneurysm surgery. Br J Surg 2007;94:717–21.34. Drury D, Michaels JA, Jones L, Ayiku L. Systematicreview of recent evidence for the safety and efficacyof elective endovascular repair in the managementof infrarenal abdominal aortic aneurysm. Br J Surg2005;92:937–46.35. Lederle FA, Kane RL, MacDonald R, Wilt TJ.Systematic review: repair of unruptured abdominalaortic aneurysm. Ann Intern Med 2007;146:735–41.36. Jonk YC, Kane RL, Lederle FA, MacDonaldR, Cutting AH, Wilt TJ. Cost-effectiveness ofabdominal aortic aneurysm repair: a systematicreview. Int J Technol Assess Health Care 2007;23:205–15.37. NHS Centre for Reviews and Dissemination.Undertaking systematic reviews of research oneffectiveness. CRD’s guidance for those carrying out orcommissioning reviews. 2nd edn. York: NHS Centrefor Reviews and Dissemination; 2001.38. Perel P, Edwards P, Wentz R, Roberts I. Systematicreview of prognostic models in traumatic braininjury. BMC Med Inform Decis Mak 2006;6:38.39. Tierney J, Stewart L, Ghersi D, Burdett S, Sydes M.Practical methods for incorporating summary timeto-eventdata into meta-analysis. Trials 2007;8:16.40. Prinssen M, Verhoeven ELG, Buth J, Cuypers PWM,van Sambeek MRH, Balm R, et al. A randomizedtrial comparing conventional and endovascularrepair of abdominal aortic aneurysms. N Engl J Med2004;351:1607–18.41. Blankensteijn JD, de Jong SEC, Prinssen M, van derHam AC, Buth J, van Sterkenburg SMM, et al. Twoyearoutcomes after conventional or endovascularrepair of abdominal aortic aneurysms. N Engl J Med2005;352:2398–405.42. EVAR trial participants. Comparison ofendovascular aneurysm repair with open repairin patients with abdominal aortic aneurysm(EVAR trial 1), 30-day operative mortality results:randomised controlled trial. Lancet 2004;364:843–8.43. EVAR trial participants. Endovascular aneurysmrepair versus open repair in patients withabdominal aortic aneurysm (EVAR trial 1):randomised controlled trial. Lancet 2005;365:2179–86.44. Cuypers PMW, Gardien M, Buth J, Peels CH,Charbon JA, Hop W. Randomized study comparingcardiac response in endovascular and openabdominal aortic aneurysm repair. Br J Surg2001;88:1059–65.45. Soulez G, Thérasse E, Monfared AA, Blair JF,Choiniére M, Elkouri S, et al. Pain and quality of lifeassessment after endovascular versus open repair ofabdominal aortic aneurysms in patients at low risk. JVasc Interv Radiol 2005;16:1093–100.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 4846. EVAR trial participants. Endovascular aneurysmrepair and outcome in patients unfit for openrepair of abdominal aortic aneurysm (EVAR trial 2):randomised controlled trial. Lancet 2005;365:2187–92.47. Hinchliffe RJ, Bruijstens L, MacSweeney ST,Braithwaite BD. A randomised trial of endovascularand open surgery for ruptured abdominal aorticaneurysm – results of a pilot study and lessonslearned for future studies. Eur J Vasc Endovasc Surg2006;32:506–13.48. Amsterdam Acute Aneurysm Trial Collaborators.Amsterdam Acute Aneurysm Trial: background,design, and methods. Vascular 2006;14:130–5.49. ACE. Elective abdominal aortic aneurysm – openversus endovascular repair. URL: www.controlledtrials.com.Accessed 11 September 2007.50. Standard open surgery versus endovascular repairof abdominal aortic aneurysm (AAA). URL: www.controlled-trials.com. Accessed 11 September 2007.51. NExT ERA: National Expertise Based Trial ofElective Repair of Abdominal Aortic Aneurysms:a pilot study. URL: www.controlled-trials.com.Accessed 11 September 2007.52. Cao P. Comparison of surveillance vs AorticEndografting for Small Aneurysm Repair (CAESAR)trial: study design and progress. Eur J Vasc EndovascSurg 2005;30:245–51.53. Liapis CD, Kakisis JD. Value of registries for EVAR.Eur J Vasc Endovasc Surg 2005;30:341–2.54. EUROSTAR collaborators. Progress report: endograftsin current use only (Anaconda, Ancure, AneuRx,Endologix, Excluder, Fotron, Lifepath, Talent & Zenith).Eindhoven, the Netherlands: EUROSTAR DataRegistry Centre; 2006.55. Harris PL, Buth J, Mialhe C, Myhre HO, NorgrenL. The need for clinical trials of endovascularabdominal aortic aneurysm stent-graft repair: theEUROSTAR project. J Endovasc Surg 1997;4:72–7.56. Thomas SM, Beard JD, Ireland M, Ayers S. Resultsfrom the prospective Registry of EndovascularTreatment of Abdominal Aortic Aneurysms (RETA):mid term results to five years. Eur J Vasc EndovascSurg 2005;29:563–70.57. Vascular Surgical Society of Great Britain andIreland, British Society of Interventional Radiology.Fifth report on the Registry for Endovascular Treatmentof Aneurysms (RETA). A patient cohort of 1000endovascular aneurysm repairs for AAA (undated).URL: www.vascularsociety.org.uk/docs/5thretareport.pdf. Accessed 9 June 2009.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.58. Thomas SM, Gaines PA, Beard JD. Short-term(30-day) outcome of endovascular treatment ofabdominal aortic aneurysm: results from theprospective registry of endovascular treatment ofabdominal aortic aneurysms (RETA). Eur J VascEndovasc Surg 2001;21:57–64.59. Biancari F, Hobo R, Juvonen T. Glasgow AneurysmScore predicts survival after endovascular stentingof abdominal aortic aneurysm in patients from theEUROSTAR registry. Br J Surg 2006;93:191–4.60. Boult M, Maddern G, Barnes M, Fitridge R. Factorsaffecting survival after endovascular aneurysmrepair: results from a population based audit. Eur JVasc Endovasc Surg 2007;34:156–62.61. Brewster DC, Jones JE, Chung TK, Lamuraglia GM,Kwolek CJ, Watkins MT, et al. Long-term outcomesafter endovascular abdominal aortic aneurysmrepair – the first decade. Ann Surg 2006;244:426–38.62. Bush RL, Johnson ML, Hedayati N, HendersonWG, Lin PH, Lumsden AB. Performance ofendovascular aortic aneurysm repair in high-riskpatients: results from the Veterans Affairs NationalSurgical Quality Improvement Program. J Vasc Surg2007;45:227–33.63. Buth J. Endovascular repair of abdominal aorticaneurysms. Results from the EUROSTAR registry.EUROpean collaborators on Stent-graft Techniquesfor abdominal aortic Aneurysm Repair. Semin IntervCardiol 2000;5:29–33.64. Buth J, Laheij RJF. Early complications andendoleaks after endovascular abdominal aorticaneurysm repair: report of a multicenter study. JVasc Surg 2000;31:134–45.65. Buth J, van Marrewijk CJ, Harris PL, Hop WCJ,Riambau V, Laheij RJF. Outcome of endovascularabdominal aortic aneurysm repair in patients withconditions considered unfit for an open procedure:a report on the EUROSTAR experience. J Vasc Surg2002;35:211–19.66. Buth J, Harris PL, van Marrewijk C, Fransen G. Thesignificance and management of different types ofendoleaks. Semin Vasc Surg 2003;16:95–102.67. Cuypers PW, Laheij RJ, Buth J. Which factorsincrease the risk of conversion to open surgeryfollowing endovascular abdominal aortic aneurysmrepair? The EUROSTAR collaborators. Eur J VascEndovasc Surg 2000;20:183–9.68. Diehm N, Hobo R, Baumgartner I, Do DD, KeoHH, Kalka C, et al. Influence of pulmonary statusand diabetes mellitus on aortic neck dilatationfollowing endovascular repair of abdominal aortic149

References150aneurysms: a EUROSTAR report. J Endovasc Ther2007;14:122–9.69. Hobo R, Buth J. Secondary interventions followingendovascular abdominal aortic aneurysm repairusing current endografts. A EUROSTAR report. JVasc Surg 2006;43:896–902.70. Hobo R, Kievit J, Leurs LJ, Buth J. Influenceof severe infrarenal aortic neck angulation oncomplications at the proximal neck followingendovascular AAA repair: a EUROSTAR study. JEndovasc Ther 2007;14:1–11.71. Lange C, Leurs LJ, Buth J, Myhre HO, Eurostarcollaborators. Endovascular repair of abdominalaortic aneurysm in octogenarians: an analysis basedon EUROSTAR data. J Vasc Surg 2005;42:624–30.72. Leurs LJ, Buth J, Harris PL, BlankensteijnJD. Impact of study design on outcome afterendovascular abdominal aortic aneurysm repair.A comparison between the randomized controlledDREAM-trial and the observational EUROSTARregistry.Eur J Vasc Endovasc Surg 2007;33:172–6.73. Leurs LJ, Hobo R, Buth J. The multicenterexperience with a third-generation endovasculardevice for abdominal aortic aneurysm repair – areport from the EUROSTAR database. J CardiovascSurg 2004;45:293–300.74. Leurs LJ, Kievit J, Dagnelie PC, Nelemans PJ, ButhJ. Influence of infrarenal neck length on outcomeof endovascular abdominal aortic aneurysm repair. JEndovasc Ther 2006;13:640–8.75. Leurs LJ, Laheij RJF, Buth J. Influence ofdiabetes mellitus on the endovascular treatmentof abdominal aortic aneurysms. J Endovasc Ther2005;12:288–96.76. Leurs LJ, Stultiens G, Kievit J, Buth J. Adverseevents at the aneurysmal neck identified atfollow-up after endovascular abdominal aorticaneursym repair: how do they correlate? Vascular2005;13:261–7.77. Leurs LJ, Visser P, Laheij RJF, Buth J, Harris PLH,Blankensteijn JD. Statin use is associated withreduced all-cause mortality after endovascularabdominal aortic aneurysm repair. Vascular2006;14:1–8.78. Lifeline Registry of Endovascular AneurysmRepair Steering Committee. Lifeline Registryof Endovascular Aneurysm Repair: registry datareport. J Vasc Surg 2002;35:616–20.79. Lifeline Registry of EVAR Publications Committee.Lifeline registry of endovascular aneurysm repair:long-term primary outcome measures. J Vasc Surg2005;42:1–10.80. Lottman P, van Marrewijk C, Fransen G, LaheijR, Buth J. Impact of smoking on endovascularabdominal aortic aneurysm surgery outcome. Eur JVasc Endovasc Surg 2004;27:512–18.81. Mohan IV, Laheij RJ, Harris PL; Eurostarcollaborators. Risk factors for endoleak and theevidence for stent-graft oversizing in patientsundergoing endovascular aneurysm repair. Eur JVasc Endovasc Surg 2001;21:344–9.82. Peppelenbosch N, Buth J, Harris PL, vanMarrewijk C, Fransen G. Diameter of abdominalaortic aneurysm and outcome of endovascularaneurysm repair: does size matter? A report fromEUROSTAR. J Vasc Surg 2004;39:288–97.83. Riambau V, Laheij RJ, Garcia-Madrid C, Sanchez-Espin G, Eurostar group. The association betweenco-morbidity and mortality after abdominal aorticaneurysm endografting in patients ineligible forelective open surgery. Eur J Vasc Endovasc Surg2001;22:265–70.84. Ruppert V, Leurs LJ, Steckmeier B, Buth J,Umscheid T. Influence of anesthesia type onoutcome after endovascular aortic aneurysm repair:an analysis based on EUROSTAR data. J Vasc Surg2006;44:16–21.85. Sampram ESK, Karafa MT, Mascha EJ, Clair DG,Greenberg RK, Lyden SP, et al. Nature, frequency,and predictors of secondary procedures afterendovascular repair of abdominal aortic aneurysm.J Vasc Surg 2003;37:930–7.86. Timaran CH, Veith FJ, Rosero EB, Modrall JG,Arko FR, Clagett GP, et al. Endovascular aorticaneurysm repair in patients with the highest riskand in-hospital mortality in the United States. ArchSurg 2007;142:520–4.87. Torella F. Effect of improved endograft design onoutcome of endovascular aneurysm repair. J VascSurg 2004;40:216–21.88. van Eps RGS, Leurs LJ, Hobo R, Harris PL, Buth J.Impact of renal dysfunction on operative mortalityfollowing endovascular abdominal aortic aneurysmsurgery. Br J Surg 2007;94:174–8.89. van Marrewijk CJ, Fransen G, Laheij RJF, HarrisPL, Buth J. Is a type II endoleak after EVAR aharbinger of risk? Causes and outcome of openconversion and aneurysm rupture during follow-up.Eur J Vasc Endovasc Surg 2004;27:128–37.90. Zarins CK, Crabtree T, Bloch DA, Arko FR, OurielK, White RA. Endovascular aneurysm repair at 5

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48years: does aneurysm diameter predict outcome? JVasc Surg 2006;44:920–9.91. Diehm N, Benenati JF, Becker GJ, Quesada R,Tsoukas AI, Katzen BT, et al. Anemia is associatedwith abdominal aortic aneurysm (AAA) size anddecreased long-term survival after endovascularAAA repair. J Vasc Surg 2007;46:676–81.92. Boult M, Babidge W, Maddern G, Barnes M,Fitridge R. Predictors of success followingendovascular aneurysm repair: mid-term results.Eur J Vasc Endovasc Surg 2006;31:123–9.93. Prinssen M, Buskens E, Blankensteijn JD, on behalfof the DREAM trial participants. Quality of lifeafter endovascular and open AAA repair. Resultsof a randomised trial. Eur J Vasc Endovasc Surg2004;27:121–7.94. Lottman PEM, Laheij RJF, Cuypers PWM, BenderM, Buth J. Health-related quality of life outcomesfollowing elective open or endovascular AAA repair:a randomized controlled trial. J Endovasc Ther2004;11:323–9.95. EVAR trial participants. Secondary interventionsand mortality following endovascular aorticaneurysm repair: device-specific results fromthe UK EVAR trials. Eur J Vasc Endovasc Surg2007;34:281–90.96. Schermerhorn M, O’Malley A, Jhaveri A, CotterillP, Pomposelli F, Landon B. Endovascular vs openrepair of abdominal aortic aneurysms in theMedicare population. N Engl J Med 2008;358:464–74.97. Drummond M, Jefferson T. Guidelines for authorsand peer reviewers of economic submissions to theBMJ. BMJ 1996;313:275–83.98. Patel AP, Langan EM, Taylor SM, Gray BH, CarstenCG, Cull DL, et al. An analysis of standard open andendovascular surgical repair of abdominal aorticaneurysms in octogenarians. Am Surg 2003;69:744–7.99. Blum U, Voshage G, Lammer J, Beyersdorf F,Töllner D, Kretschmer G, et al. Endoluminal stentgraftsfor infrarenal abdominal aortic aneurysms. NEngl J Med 1997;336:13–20.100. Goldstone J, Brewster DC, Chaikof EL, Katzen BT,Moore WS, Pearce WH. Endoluminal repair versusstandard open repair of abdominal aortic aneurysm:early results of a prospective clinical comparisontrial. In Proceedings of the 46th Scientific Meetingof the International Society for CardiovascularSurgery, San Diego, CA, 7–10 June 1998.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.101. Zarins CK, White RA, Schwarten DE, Kinney EV,Diethrich EB, Hodgson KJ, et al. Medtronic AneuRxstent graft system versus open surgical repair ofAAA: multicenter clinical trial. In Proceedings ofthe 46th Scientific Meeting of the InternationalSociety for Cardiovascular Surgery, San Diego, CA,7–10 June 1998.102. Johnston KW. Multicenter prospective study ofnonruptured abdominal aortic aneurysm. Part II.Variables predicting morbidity and mortality. J VascSurg 1989;9:437–47.103. Mialhe C, Amicabile C, Becquemin JP. Endovasculartreatment of infrarenal abdominal aneurysms bythe Stentor system: preliminary results of 79 cases.Stentor Retrospective Study Group. J Vasc Surg1997;26:199–209.104. Jacobowitz GR, Lee AM, Riles TS. Immediate andlate explantation of endovascular aortic grafts:the EVT experience. In Proceedings of the 46thScientific Meeting of the International Society forCardiovascular Surgery, San Diego, CA, 7–10 June1998.105. Patel ST, Haser PB, Bush HL, Jr, Kent KC. The costeffectivenessof endovascular repair versus opensurgical repair of abdominal aortic aneurysms: adecision analysis model. J Vasc Surg 1999;29:958–72.106. Epstein D, Sculpher MJ, Manca A, Michaels JA,Thompson SG, Brown LC, et al. Modelling the longtermcost-effectiveness of endovascular or openrepair for abdominal aortic aneurysm. Br J Surg2008;94:183–90.107. Michaels JA, Drury D, Thomas SM. Costeffectivenessof endovascular abdominal aorticaneurysm repair. Br J Surg 2005;92:960–7.108. Bosch JL, Kaufman JA, Beinfeld MT, AdriaensenMEAPM, Brewster DC, Gazelle GS. Abdominalaortic aneurysms: cost-effectiveness of electiveendovascular and open surgical repair. Radiology2002;225:337–44.109. Birch SE, Stary DR, Scott AR. Cost of endovascularversus open surgical repair of abdominal aorticaneurysms. Aust N Z J Surg 2000;70:660–6.110. Brewster DC, Geller SC, Kaufman JA, Cambria RP,Gertler JP, LaMuraglia GM, et al. Initial experiencewith endovascular aneurysm repair: comparisonof early results with outcome of conventional openrepair. J Vasc Surg 1998;27:992–1003.111. Cohnert TU, Oelert F, Wahlers T, Gohrbandt B,Chavan A, Farber A, et al. Matched-pair analysis ofconventional versus endoluminal AAA treatmentoutcomes during the initial phase of an aortic151

References152endografting program. J Endovasc Ther 2000;7:94–100.112. May J, White GH, Yu W, Ly CN, Waugh R, StephenMS, et al. Concurrent comparison of endoluminalversus open repair in the treatment of abdominalaortic aneurysms: analysis of 303 patients by lifetable method. J Vasc Surg 1998;27:213–20.113. Moore WS, Kashyap VS, Vescera CL, Quinones-Baldrich WJ. Abdominal aortic aneurysm – a 6-yearcomparison of endovascular versus transabdominalrepair. Ann Surg 1999;230:298–306.114. Scharrer-Pamler R, Kapfer X, Orend KH,Sunder-Plassmann L. Endoluminal grafting ofinfrarenal aortic aneurysms. Thorac Cardiovasc Surg1999;47:119–21.115. Treharne GD, Thompson MM, Whiteley MS,Bell PR. Physiological comparison of openand endovascular aneurysm repair. Br J Surg1999;86:760–4.116. Zarins CK, White RA, Schwarten D, Kinney E,Diethrich EB, Hodgson KJ, et al. AneuRx stent graftversus open surgical repair of abdominal aorticaneurysms: multicenter prospective clinical trial. JVasc Surg 1999;29:292–306.117. Adriaensen MEAPM, Bosch JL, Halpern EF,Hunink MGM, Gazelle GS. Elective endovascularversus open surgical repair of abdominal aorticaneurysms: systematic review of short-term results.Radiology 2002;224:739–47.118. Harris PL, Vallabhaneni SR, Desgranges P,Bacquemin JP, van Marrewijk C, Laheij RJF.Incidence and risk factors of late rupture,conversion, and death after endovascular repairof infrarenal aortic aneurysms: the EUROSTARexperience. J Vasc Surg 2000;32:739–49.119. Zarins CK, White RA, Moll FL, Crabtree T, BlochDA, Hodgson KJ, et al. The AneuRx stent graft:four-year results and worldwide experience 2000. JVasc Surg 2001;33:S135–45.120. Hallett JW, Jr, Marshall DM, Petterson TM, GrayDT, Bower TC, Cherry KJ, Jr, et al. Graft-relatedcomplications after abdominal aortic aneurysmrepair: reassurance from a 36-year population-basedexperience. J Vasc Surg 1997;25:277–86.121. Drury D, Michaels J, Jones L, Ayiku L. NationalInstitute of Clinical Excellence review body report: asystematic review of the recent evidence for the safety andefficacy of elective endovascular repair in the managementof infrarenal abdominal aortic aneurysms. London:National Institute of Clinical Excellence; 2004.122. Prescott-Clarke P, Primatesta P, editors. HealthSurvey for England ’96. A survey carried out on behalfof the Department of Health by the Joint Health SurveysUnit of Social and Community Planning Research(SCPR) and the Department of Epidemiology and PublicHealth, University College London. London: StationeryOffice; 1998. URL: www.archive.official-documents.co.uk/document/doh/survey96/ehtitle.htm.123. Department of Health. NHS reference costs 2003 andNational tariff 2004. London: Department of Health;2004.124. Becquemin JP, Allaire E, Cavillon A, DesgrangesP, Melliere D. Conventional versus endovascularsurgical procedures: a no choice option. Eur J VascEndovasc Surg 1995;10:1–3.125. Jones L, Griffin S, Palmer S, Main C, Orton V,Sculpher M, et al. Clinical effectiveness and costeffectivenessof clopidogrel and modified-releasedipyridamole in the secondary prevention ofocclusive vascular events: a systematic review andeconomic evaluation. Health Technol Assess 2004;8:1–196.126. Prinssen M, Buskens E, de Jong S, Buth J,Mackaay A, Sambeek M, et al. Cost-effectiveness ofconventional and endovascular repair of abdominalaortic aneurysms: results of a randomized trial. JVasc Surg 2007;46:883–90.127. Medtronic. Endovascular aneurysm repair (EVAR) forthe treatment of infra-renal abdominal aortic aneurysms(AAA). A submission to the National Institutefor Health and Clinical Excellence (NICE) byMedtronic; 2007.128. Bowen J, De Rose G, Hopkins R, Novick T,Blackhouse G, Tarride JE, et al. Systematic review andcost-effectiveness analysis of elective endovascular repaircompared to open surgical repair of abdominal aorticaneurysms. Hamilton, Canada: McMaster University;2005.129. Bowen J, De Rose G, Novick T, Blackhouse G,Hopkins R, Tarride JE, et al. Systematic review andcost-effectiveness analysis of elective endovascular repaircompared to open surgical repair of abdominal aorticaneurysms. Final report. Prepared for the OntarioMinistry of Health and Long-term Care. Hamilton,Canada: McMaster University; 2007.130. Cronenwett JL, Murphy TF, Zelenock GB,Whitehouse WM, Jr, Lindenauer SM, GrahamLM, et al. Actuarial analysis of variables associatedwith rupture of small abdominal aortic aneurysms.Surgery 1985;98:472–83.131. Bernstein EF, Chan EL. Abdominal aortic aneurysmin high-risk patients. Outcome of selective

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48management based on size and expansion rate. AnnSurg 1984;200:255–63.132. Nevitt MP, Ballard DJ, Hallett JW, Jr. Prognosis ofabdominal aortic aneurysms. A population-basedstudy. N Engl J Med 1989;321:1009–14.133. Collin J, Araujo L, Walton J. How fast do very smallabdominal aortic aneurysms grow? Eur J Vasc Surg1989;3:5–7.134. Walsh AK, Briffa N, Nash JR, Callum KG.The natural history of small abdominal aorticaneurysms: an ultrasound study. Eur J Vasc Surg1990;4:459–61.135. Glimåker H, Holmberg L, Elvin A, Nybacka O,Almgren B, Björck CG, et al. Natural history ofpatients with abdominal aortic aneurysm. Eur J VascSurg 1991;5:125–30.136. Bergqvist D, Bengtsson H. Risk factors for ruptureof abdominal aortic aneurysm. Clinical review. ActaChir Scand 1990;156:63–8.137. Cronenwett JL, Sargent SK, Wall MH, Hawkes ML,Freeman DH, Dain BJ, et al. Variables that affect theexpansion rate and outcome of small abdominalaortic aneurysms. J Vasc Surg 1990;11:260–9.138. Heather B, Collin J, Walton J. Optimumrescreening interval for abdominal aortic aneurysm.Br J Surg 1991;78:365.139. Delin A, Ohlsén H, Swedenborg J. Growth rateof abdominal aortic aneurysms as measured bycomputed tomography. Br J Surg 1985;72:530–2.140. Bernstein EF, Dilley RB, Goldberger LE, GosinkBB, Leopold GR. Growth rates of small abdominalaortic aneurysms. Surgery 1976;80:765–73.141. Sakalihasan N, Limet R, Defawe OD. Abdominalaortic aneurysm. Lancet 2005;365:1577–89.142. Greenhalgh R, Brown L, Powell J. High risk andunfit for open repair are not the same. Eur J VascEndovasc Surg 2007;34:154–5.143. HM Treasury. The Green Book: appraisal andevaluation in central government. London: HMTreasury; 2003.144. Government Actuary’s Department. Interim lifetables. Expectation of life for males in the UnitedKingdom, based on data for the years 2004–2006. URL:www.gad.gov.uk. Cited December 2007.145. Office for National Statistics. Mortality statistics: cause.Review of the Registrar General on deaths by cause, sexand age, in England and Wales, 2004. Series DH2 No.31. London: Office for National Statistics; 2005.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.146. Brady AR, Thompson SG, Gerald F, Fowkes R,Greenhalgh RM, Powell JT, et al. Abdominal aorticaneurysm expansion: risk factors and time intervalsfor surveillance. Circulation 2004;110:16–21.147. Information Services Division (ISD Scotland). Costbook 2006. 2006. URL: www.isdscotland.org/isd/797.html. Cited 18 March 2008.148. Department of Health. NHS reference costs2006–07. 2006. URL: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_082571. Cited18 March 2008.149. National Blood Service. National prices 2004/2005:impact of major developments. London: National BloodService; 2004.150. Kind P, Hardman G. UK population norms forEQ5D. Report No. 172. York: Centre for HealthEconomics; 1999.151. Drummond MF, Sculpher MJ, Torrance GW,O’Brien BJ, Stewart GL. Methods for the economicevaluation of health care programmes. 3rd edn. Oxford:Oxford University Press; 2005.152. Stinnett A, Mullahy J. Net health benefits: anew framework for the analysis of uncertaintyin cost-effectiveness analysis. Med Decis Making1998;18:S68–80.153. Spiegelhalter D, Abrams K. Bayesian approachesto clinical trials and health care evaluation. London:Wiley; 2004.154. Powell J, Brown L, Greenhalgh R, Thompson S,EVAR trial participants. The rupture rate of largeabdominal aortic aneurysms: is this modified byanatomical suitability for endovascular repair? AnnSurg 2008;247:173–9.155. Brown PM, Zelt DT, Sobolev B. The risk of rupturein untreated aneurysms: the impact of size, gender,and expansion rate. J Vasc Surg 2003;37:280–4.156. Limet R, Sakalihassan N, Albert A. Determinationof the expansion rate and incidence of ruptureof abdominal aortic aneurysms. J Vasc Surg1991;14:540–8.157. Reed WW, Hallett JW, Jr, Damiano MA, Ballard D.Learning from the last ultrasound: a populationbasedstudy of patients with abdominal aorticaneurysm. Arch Intern Med 1997;157:2064–8.158. The UK Small Aneurysm Trial Participants.Mortality results for randomised controlled trialof early elective surgery or ultrasonographicsurveillance for small abdominal aortic aneurysms.Lancet 1998;352:1649–55.153

References154159. Kim LG, Thompson SG, Briggs AH, BuxtonMJ, Campbell HE. Evaluating the long-termcost-effectiveness of screening for abdominal aorticaneurysms: development and validation of a Markovmodel. Technical Report 2005/2. Cambridge: MRCBiostatistics Unit; 2005.160. Jones A, Cahill D, Gardham R. Outcome in patientswith large abdominal aortic aneurysm consideredunfit for surgery. Br J Surg 1998;85:1382–4.161. Brown LC, Powell JT. Risk factors for aneurysmrupture in patients kept under ultrasoundsurveillance. Ann Surg 1999;230:289–97.162. Conway KP, Byrne J, Townsend M, LaneIF. Prognosis of patients turned down forconventional abdominal aortic aneurysm repairin the endovascular and sonographic era: Szilagyirevisited? J Vasc Surg 2001;33:752–7.163. Lederle FA, Johnson GR, Wilson SE, Ballard DJ,Jordan WD, Jr, Blebea J, et al. Rupture rate of largeabdominal aortic aneurysms in patients refusing orunfit for elective repair. JAMA 2002;287:2968–72.164. Aziz M, Hill AA, Bourchier R. Four-year followup of patients with untreated abdominal aorticaneurysms. Aust N Z J Surg 2004;74:935–40.165. Bellman RE. Dynamic programming. Princeton, NJ:Princeton University Press; 1957.166. Fotis T, Tsoumakidou G, Katostaras T, KalokairinouA, Konstantinou E, Vozides K, et al. Cost andeffectiveness comparison of endovascular aneurysmrepair versus open surgical repair of abdominalaortic aneurysm. J Vasc Nurs 2008;26:15–21.167. Mani K, Bjorck M, Lundkvist J, Wanhainen A.Similar cost for elective open and endovascular AAArepair in a population-based setting. J Endovasc Ther2008;15:1–11.168. Henebiens M, van den Broek TAA, Vahl AC,Koelemay MJW. Relation between hospital volumeand outcome of elective surgery for abdominalaortic aneurysm: a systematic review. Eur J VascEndovasc Surg 2007;33:285–92.169. Prinssen M, Buskens E, Blankensteijn JD. TheDutch Randomised Endovascular AneurysmManagement (DREAM) trial. Background, designand methods. J Cardiovasc Surg 2002;43:379–84.170. Prinssen M, Buskens E, Nolthenius RPT, vanSterkenburg SMM, Teijink JAW, BlankensteijnJD. Sexual dysfunction after conventional andendovascular AAA repair: results of the DREAMtrial. J Endovasc Ther 2004;11:613–20.171. Greenhalgh RM. Do results of the EVAR 1 trialjustify endovascular repair of all abdominal aorticaneurysms in patients with suitable anatomy.Vascular 2005;13:S30–1.172. Polakow P, Lukasiewicz A, Kordecki K, Polakaw J,Janica J. Comparison of endovascular aneurysmrepair with open repair in patients wih abdominalaortic aneurysm. [Polish]. Pol J Radiol 2006;71:97–102.173. Akert A, Zingg E, Schmidli J, Heller G, WidmerMK, Eigenmann V, et al. No increase in mortalityafter open infrarenal aortic surgery in the era ofEVAR. Int J Angiol 2004;13:116–19.174. Almagor Y. First International NIR EndovascularStent Study (FINESS): acute results and 6-monthsfollow-up. Asia Pacific Heart J 1997;6:64.175. Bell RE, Buth J, Taylor PR, Harris P, Fransen G,Thomas S, et al. UK and EUROSTAR thoracicstenting registries: combined experience. J EndovascTher 2004;11:6.176. Dawkins KD, Colombo A, Verheye S, Dens J,Thomas M, Schuhlen H, et al. European pivotaltrial with the CoStar Stent loaded with anantiproliferative for restenosis trial (EuroSTAR):final 12 month results. Eur Heart J 2006;27:767.177. Dawkins KD, Columbo A, Verheye S, Dens J,Thomas M, Schuhlen H, et al. Final results oftwo arm European pivotal trial with CoStar Stent(EuroSTAR): 6 and 12 month outcome. J Am CollCardiol 2006;47:38B–39B.178. DeRubertis BG, Trocciola SM, Ryer EJ, PieracciFM, McKinsey JF, Faries PL, et al. Abdominal aorticaneurysm in women: prevalence, risk factors, andimplications for screening. J Vasc Surg 2007;46:630–5.179. Eyraud D, Bertrand M, Fleron MH, Godet G, RiouB, Kieffer E, et al. [Risk factors for mortality inabdominal aortic surgery]. Ann Fr Anesth Reanim2000;19:452–8.180. Faggioli G, Stella A, Freyrie A, Gargiulo M,Tarantini S, Rodio M, et al. Early and long-termresults in the surgical treatment of juxtarenal andpararenal aortic aneurysms. Eur J Vasc Endovasc Surg1998;15:205–11.181. Gotohda N, Iwagaki H, Itano S, Horiki S, FujiwaraT, Saito S, et al. Can POSSUM, a scoring system forperioperative surgical risk, predict postoperativeclinical course? Acta Med Okayama 1998;52:325–9.182. Hamdan AD, Saltzberg SS, Sheahan M, Froelich J,Akbari CM, Campbell DR, et al. Lack of associationof diabetes with increased postoperative mortality

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48and cardiac morbidity: results of 6565 majorvascular operations. Arch Surg 2002;137:417–21.183. Huber TS, Harward TR, Flynn TC, Albright JL,Seeger JM. Operative mortality rates after electiveinfrarenal aortic reconstructions. J Vasc Surg1995;22:287–93.184. Hutter MM, Lancaster RT, Henderson WG, KhuriSF, Mosca C, Johnson RG, et al. Comparisonof risk-adjusted 30-day postoperative mortalityand morbidity in Department of Veterans Affairshospitals and selected university medical centers:vascular surgical operations in men. J Am Coll Surg2007;204:1115–26.185. LeMaire SA, Miller CC, III, Conklin LD,Schmittling ZC, Koksoy C, Coselli JS. A newpredictive model for adverse outcomes after electivethoracoabdominal aortic aneurysm repair. AnnThorac Surg 2001;71:1233–8.186. Leurs LJ, Bell R, Degrieck Y, Thomas S, Hobo R,Lundbom J. Endovascular treatment of thoracicaortic diseases: combined experience from theEUROSTAR and United Kingdom ThoracicEndograft registries. J Vasc Surg 2004;40:670–9.187. Leurs LJ, Harris PL, Buth J. Secondaryinterventions after elective endovascular repair ofdegenerative thoracic aortic aneurysms: results ofthe European Collaborators Registry (EUROSTAR).J Vasc Interv Radiol 2007;18:491–5.188. Prytherch DR, Ridler BM, Beard JD, EarnshawJJ, Audit and Research Committee, The VascularSurgery Society of Great Britain and Ireland. Amodel for national outcome audit in vascularsurgery. Eur J Vasc Endovasc Surg 2001;21:477–83.189. Salenius JP, FINNVASC Study Group. Nationalvascular registry in Finland – FINNVASC. Ann ChirGynaecol 1992;81:257–60.190. Schouten O, van Waning VH, Kertai MD, FeringaHHH, Bax JJ, Boersma E, et al. Perioperative andlong-term cardiovascular outcomes in patientsundergoing endovascular treatment comparedwith open vascular surgery for abdominal aorticaneurysm or iliaco-femoro-popliteal bypass. Am JCardiol 2005;96:861–6.191. West CA, Noel MA, Bower TC, Cherry KJ, GloviczkiP, Sullivan TM, et al. Factors affecting outcomes ofopen surgical repair of pararenal aortic aneurysms:a 10-year experience. J Vasc Surg 2006;43:921–7.192. Smoking, lung function and the prognosis ofabdominal aortic aneurysm. The UK SmallAneurysm Trial Participants. Eur J Vasc EndovascSurg 2000;19:636–42.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.193. Ashton HA, Gao L, Kim LG, Druce PS,Thompson SG, Scott RAP. Fifteen-year follow-upof a randomized clinical trial of ultrasonographicscreening for abdominal aortic aneurysms. Br J Surg2007;94:696–701.194. Laohapensang K, Rerkasem K, Chotirosniramit N.Mini-laparotomy for repair of infrarenal abdominalaortic aneurysm. Int Angiol 2005;24:238–44.195. Lindholt JS, Juul S, Fasting H, Henneberg EW.Preliminary ten year results from a randomisedsingle centre mass screening trial for abdominalaortic aneurysm. Eur J Vasc Endovasc Surg2006;32:608–14.196. Lindholt JS, Juul S, Henneberg EW. High-risk andlow-risk screening for abdominal aortic aneurysmboth reduce aneurysm-related mortality. A stratifiedanalysis from a single-centre randomised screeningtrial. J Vasc Surg 2007;46:174–5.197. Powell JT, Brown LC, Forbes JF, Fowkes FGR,Greenhalgh RM, Ruckley CV, et al. Final 12-yearfollow-up of surgery versus surveillance in the UKSmall Aneurysm Trial. Br J Surg 2007;94:702–8.198. UK Small Aneurysm Trial Participants. Final twelfthyearfollow-up of surgery vs surveillance in the UKSmall Aneurysm Trial. J Vasc Surg 2007;46:824.199. Akkersdijk GJM, Prinssen M, Blankensteijn JD. Theimpact of endovascular treatment on in-hospitalmortality following non-ruptured AAA repair overa decade: a population based study of 16,446patients. Eur J Vasc Endovasc Surg 2004;28:41–6.200. Kantonen I, Lepantalo M, Salenius JP, Matzke S,Luther M, Ylonen K. Mortality in abdominal aorticaneurysm surgery – the effect of hospital volume,patient mix and surgeon’s case load. Eur J VascEndovasc Surg 1997;14:375–9.201. Sicard GA, Zwolak RM, Sidawy AN, White RA,Siami FS. Endovascular abdominal aortic aneurysmrepair: long-term outcome measures in patients athigh-risk for open surgery. J Vasc Surg 2006;44:229–36.202. Berry AJ, Smith RB, III, Weintraub WS, ChaikofEL, Dodson TF, Lumsden AB, et al. Age versuscomorbidities as risk factors for complications afterelective abdominal aortic reconstructive surgery. JVasc Surg 2001;33:345–52.203. Biancari F, Heikkinen M, Lepantalo M, Salenius JP.Glasgow Aneurysm Score in patients undergoingelective open repair of abdominal aortic aneurysm:a Finnvasc study. Eur J Vasc Endovasc Surg2003;26:612–17.155

References156204. Chahwan S, Comerota AJ, Pigott JP, ScheuermannBW, Burrow J, Wojnarowski D. Elective treatmentof abdominal aortic aneurysm with endovascularor open repair: the first decade. J Vasc Surg2007;45:258–62.205. Collins TC, Johnson M, Daley J, Henderson WG,Khuri SF, Gordon HS. Preoperative risk factors for30-day mortality after elective surgery for vasculardisease in Department of Veterans Affairs hospitals:is race important? J Vasc Surg 2001;34:634–40.206. Conrad MF, Crawford RS, Pedraza JD, BrewsterDC, LaMuraglia GM, Corey M, et al. Long-termdurability of open abdominal aortic aneurysmrepair. J Vasc Surg 2007;46:669–75.207. Dillavou ED, Muluk SC, Makaroun MS. A decade ofchange in abdominal aortic aneurysm repair in theUnited States: have we improved outcomes equallybetween men and women? J Vasc Surg 2006;43:230–8.208. Eckstein HH, Bruckner T, Heider P, Wolf O,Hanke M, Niedermeier HP, et al. The relationshipbetween volume and outcome following electiveopen repair of abdominal aortic aneurysms (AAA)in 131 German hospitals. Eur J Vasc Endovasc Surg2007;34:260–6.209. Hadjianastassiou VG, Franco L, Jerez J, EvangelouI, Goldhill D, Tekkis P, et al. Optimal prediction ofmortality after abdominal aortic aneurysm repairwith statistical models. J Vasc Surg 2006;43:467–73.210. Heller JA, Weinberg A, Arons R, Krishnasastry KV,Lyon RT, Deitch JS, et al. Two decades of abdominalaortic aneurysm repair: have we made any progress?J Vasc Surg 2000;32:1091–100.211. Hertzer NR, Mascha EJ. A personal experiencewith factors influencing survival after elective openrepair of infrarenal aortic aneurysms. J Vasc Surg2005;42:898–905.212. Hua HT, Cambria RP, Chuang SK, Stoner MC,Kwolek CJ, Rowell KS, et al. Early outcomesof endovascular versus open abdominal aorticaneurysm repair in the National Surgical QualityImprovement Program-Private Sector (NSQIP-PS).J Vasc Surg 2005;41:382–9.213. Huber TS, Wang JG, Derrow AE, Dame DA, OzakiCK, Zelenock GB, et al. Experience in the UnitedStates with intact abdominal aortic aneurysm repair.J Vasc Surg 2001;33:304–10.214. Katz DJ, Stanley JC, Zelenock GB. Genderdifferences in abdominal aortic aneurysmprevalence, treatment, and outcome. J Vasc Surg1997;25:561–8.215. Koning G, Hobo R, Laheij R, Buth J, van der VlietJ. Medication in relation to complications afterendovascular abdominal aortic aneurysm repair.Braz J Cardiovasc Surg 2006;21:149–54.216. Korhonen SJ, Ylonen K, Biancari F, Heikkinen M,Salenius JP, Lepantalo M. Glasgow Aneurysm Scoreas a predictor of immediate outcome after surgeryfor ruptured abdominal aortic aneurysm. Br J Surg2004;91:1449–52.217. Le Manach Y, Perel A, Coriat P, Godet G, BertrandM, Riou B. Early and delayed myocardial infarctionafter abdominal aortic surgery. Anesthesiology2005;102:885–91.218. Leon LR, Jr, Labropoulos N, Laredo J, RodriguezHE, Kalman PG. To what extent has endovascularaneurysm repair influenced abdominal aorticaneurysm management in the state of Illinois? J VascSurg 2005;41:568–74.219. McPhee JT, Hill JS, Eslami MH. The impact ofgender on presentation, therapy, and mortality ofabdominal aortic aneurysm in the United States,2001–2004. J Vasc Surg 2007;45:891–9.220. Menard MT, Chew DKW, Chan RK, Conte MS,Donaldson MC, Mannick JA, et al. Outcome inpatients at high risk after open surgical repairof abdominal aortic aneurysm. J Vasc Surg2003;37:285–92.221. Noel AA, Gloviczki P, Cherry KJ, Jr, Bower TC,Panneton JM, Mozes GI, et al. Ruptured abdominalaortic aneurysms: the excessive mortality rate ofconventional repair. J Vasc Surg 2001;34:41–6.222. Ouriel K. Device-specific outcomes in endovascularabdominal aneurysm repair: does the graft make adifference? Vascular 2005;13:S132–3.223. Wald R, Waikar S, Liangos O, Pereira B, ChertowG, Jaber B. Acute renal failure after endovascularvs open repair of abdominal aortic aneurysm. J VascSurg 2006;43:460–5.224. Ouriel K, Greenberg RK, Clair DG, O’HaraPJ, Srivastava SD, Lyden SP, et al. Endovascularaneurysm repair: gender-specific results. J Vasc Surg2003;38:93–8.225. Zarins CK, Bloch DA, Crabtree T, Matsumoto AH,White RA, Fogarty TJ. Stent graft migration afterendovascular aneurysm repair: importance ofproximal fixation. J Vasc Surg 2003;38:1264–72.226. Acosta S, Lindblad B, Zdanowski Z. Predictors foroutcome after open and endovascular repair ofruptured abdominal aortic aneurysms. Eur J VascEndovasc Surg 2007;33:277–84.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48227. Alonso-Perez M, Segura R, Pita S, Cal L. Operativeresults and death predictors for nonrupturedabdominal aortic aneurysms in the elderly. Ann VascSurg 2001;15:306–11.228. Alric P, Hinchliffe RJ, Picot M, Braithwaite BD,MacSweeney STR, Wenham PW, et al. Long-termrenal function following endovascular aneurysmrepair with infrarenal and suprarenal aortic stentgrafts.J Endovasc Ther 2003;10:397–405.229. Antonello M, Lepidi S, Kechagias A, Frigatti P,Tripepi A, Biancari F, et al. Glasgow Aneurysm Scorepredicts the outcome after emergency open repairof symptomatic, unruptured abdominal aorticaneurysms. Eur J Vasc Endovasc Surg 2007;33:272–6.230. Aune S. Risk factors and operative results ofpatients aged less than 66 years operated on forasymptomatic abdominal aortic aneurysm. Eur JVasc Endovasc Surg 2001;22:240–3.231. Aziz IN, Lee JT, Kopchok GE, Donayre CE, WhiteRA, de Virgilio C. Cardiac risk stratification inpatients undergoing endoluminal graft repair ofabdominal aortic aneurysm: a single-institutionexperience with 365 patients. J Vasc Surg2003;38:56–60.232. Azizzadeh A, Sanchez LA, Miller CC, III, MarineL, Rubin BG, Safi HJ, et al. Glomerular filtrationrate is a predictor of mortality after endovascularabdominal aortic aneurysm repair. J Vasc Surg2006;43:14–18.233. Becker GJ, Kovacs M, Mathison MN, Katzen BT,Benenati JF, Zemel G, et al. Risk stratificationand outcomes of transluminal endografting forabdominal aortic aneurysm: 7-year experienceand long-term follow-up. J Vasc Interv Radiol2001;12:1033–46.234. Biancari F, Leo E, Ylonen K, Vaarala MH, Rainio P,Juvonen T. Value of the Glasgow Aneurysm Score inpredicting the immediate and long-term outcomeafter elective open repair of infrarenal abdominalaortic aneurysm. Br J Surg 2003;90:838–44.235. Biebl M, Hakaim AG, Hugl B, Oldenburg WA, Paz-Fumagalli R, McKinney JM, et al. Endovascularaortic aneurysm repair with the Zenith AAAEndovascular Graft: does gender affect proceduralsuccess, postoperative morbidity, or early survival?Am Surg 2005;71:1001–8.236. Bown MJ, Cooper NJ, Sutton AJ, Prytherch D,Nicholson ML, Bell PRF, et al. The post-operativemortality of ruptured abdominal aortic aneurysmrepair. Eur J Vasc Endovasc Surg 2004;27:65–74.237. Bui H, Haukoos J, Mansury A, Donayre C, White R,de Virgilio C. Adverse perioperative cardiac event© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.predicts long-term cardiac morbidity and mortalityfollowing endoluminal abdominal aortic aneurysmrepair. J Investig Med 2003;51:S169.238. Bush HL, Jr, Hydo LJ, Fischer E, Fantini GA,Silane MF, Barie PS. Hypothermia during electiveabdominal aortic aneurysm repair: the high price ofavoidable morbidity. J Vasc Surg 1995;21:392–400.239. Calderwood R, Halka T, Haji-Michael P, Welch M.Ruptured abdominal aortic aneurysm. Is it possibleto predict outcome? Int Angiol 2004;23:47–53.240. Cao P, Verzini F, Zannetti S, De Rango P, ParlaniG, Lupattelli L, et al. Device migration afterendoluminal abdominal aortic aneurysm repair:analysis of 113 cases with a minimum follow-upperiod of 2 years. J Vasc Surg 2002;35:229–35.241. Carpenter JP, Baum RA, Barker CF, Golden MA,Velazquez OC, Mitchell ME, et al. Durability ofbenefits of endovascular versus conventionalabdominal aortic aneurysm repair. J Vasc Surg2002;35:222–8.242. Chaikof EL, Lin PH, Brinkman WT, Dodson TF,Weiss VJ, Lumsden AB, et al. Endovascular repairof abdominal aortic aneurysms – risk stratifiedoutcomes. Ann Surg 2002;235:833–9.243. Chang JK, Calligaro KD, Lombardi JP, DoughertyMJ. Factors that predict prolonged length of stayafter aortic surgery. J Vasc Surg 2003;38:335–9.244. Chiesa R, Setacci C, Tshomba Y, Marone EM,Melissano G, Bertoglio L, et al. Ruptured abdominalaortic aneurysm in the elderly patient. Acta Chir Belg2006;106:508–16.245. Cochennec F, Becquemin JP, Desgranges P,Allaire E, Kobeiter H, Roudot-Thoraval F. Limbgraft occlusion following EVAR: clinical pattern,outcomes and predictive factors of occurrence. Eur JVasc Endovasc Surg 2007;34:59–65.246. Conners MS, III, Sternbergh WC, III, Carter G,Tonnessen BH, Yoselevitz M, Money SR. Endograftmigration one to four years after endovascularabdominal aortic aneurysm repair with the AneuRxdevice: a cautionary note. J Vasc Surg 2002;36:476–84.247. Cuypers P, Nevelsteen A, Buth J, Hamming J,Stockx L, Lacroix H, et al. Complications in theendovascular repair of abdominal aortic aneurysms:a risk factor analysis. Eur J Vasc Endovasc Surg1999;18:245–52.248. Dawson J, Vig S, Choke E, Blundell J, Horne G,Downham C, et al. Medical optimisation can reducemorbidity and mortality associated with elective157

References158aortic aneurysm repair. Eur J Vasc Endovasc Surg2007;33:100–4.249. de Virgilio C, Bui H, Donayre C, Ephraim L,Lewis RJ, Elbassir M, et al. Endovascular vs openabdominal aortic aneurysm repair – a comparisonof cardiac morbidity and mortality. Arch Surg1999;134:947–50.250. de Virgilio C, Romero L, Donayre C, Meek K, LewisRJ, Lippmann M, et al. Endovascular abdominalaortic aneurysm repair with general versus localanesthesia: a comparison of cardiopulmonarymorbidity and mortality rates. J Vasc Surg2002;36:988–91.251. de Virgilio C, Tran J, Lewis R, Donayre C, DauphineC, White R, et al. Factors affecting long-termmortality after endovascular repair of abdominalaortic aneurysms. Arch Surg 2006;141:905–9.252. de Virgilio C, Tran JK, Donayre C, Lewis R,Dauphine C, Bui H, et al. Factors affectinglong-term mortality after endovascular repairof abdominal aortic aneurysms. J Investig Med2006;54:S170.253. Dias NV, Resch T, Malina M, Lindblad B, IvancevK. Intraoperative proximal endoleaks duringAAA stent-graft repair: evaluation of risk factorsand treatment with Palmaz stents. J Endovasc Ther2001;8:268–73.254. Elkouri S, Gloviczki P, McKusick MA, PannetonJM, Andrews J, Bower TC, et al. Perioperativecomplications and early outcome after endovascularand open surgical repair of abdominal aorticaneurysms. J Vasc Surg 2004;39:497–505.255. Fairman RM, Nolte L, Snyder SA, Chuter TA,Greenberg RK, Zenith I. Factors predictive ofearly or late aneurysm sac size change followingendovascular repair. J Vasc Surg 2006;43:649–56.256. Forbes TL, Lawlor DK, DeRose G, Harris KA.Gender differences in relative dilatation ofabdominal aortic aneurysms. Ann Vasc Surg2006;20:564–8.257. Golledge J, Parr A, Boult M, Maddern G,Fitridge R. The outcome of endovascular repairof small abdominal aortic aneurysms. Ann Surg2007;245:326–33.258. Greenberg RK, Clair D, Srivastava S, BhandariG, Turc A, Hampton J, et al. Should patients withchallenging anatomy be offered endovascularaneurysm repair? J Vasc Surg 2003;38:990–6.259. Harris JR, Forbes TL, Steiner SH, Lawlor DK,Derose G, Harris KA. Risk-adjusted analysis of earlymortality after ruptured abdominal aortic aneurysmrepair. J Vasc Surg 2005;42:387–91.260. Haug ES, Romundstad P, Aune S, Hayes TBJ,Myhre HO. Elective open operation for abdominalaortic aneurysm in octogenarians – survivalanalysis of 105 patients. Eur J Vasc Endovasc Surg2005;29:489–95.261. Haulon S, Devos P, Willoteaux S, Mounier-VehierC, Sokoloff A, Halna P, et al. Risk factors of earlyand late complications in patients undergoingendovascular aneurysm repair. Eur J Vasc EndovascSurg 2003;25:118–24.262. Higashiura W, Greenberg RK, Katz E, Geiger L,Bathurst S. Predictive factors, morphologic effects,and proposed treatment paradigm for type IIendoleaks after repair of infrarenal abdominalaortic aneurysms. J Vasc Interv Radiol 2007;18:975–81.263. Ho P, Cheng SWK, Ting ACW, Poon JTC.Improvement of mortality of ruptured abdominalaortic aneurysm patients over 12 years and itsrelationship with tracheostomy. Ann Vasc Surg2006;20:175–82.264. Hovsepian DM, Hein AN, Pilgram TK, Cohen DT,Kim HS, Sanchez LA, et al. Endovascular abdominalaortic aneurysm repair in 144 patients: correlationof aneurysm size, proximal aortic neck length, andprocedure-related complications. J Vasc Interv Radiol2001;12:1373–82.265. Hugl B, Hakaim AG, Biebl M, Oldenburg WA,McKinney JM, Nolte LA, et al. Impact of genderon the outcome of endovascular aortic aneurysmrepair using the Zenith stent-graft: midterm results.J Endovasc Ther 2007;14:115–21.266. Jordan WD, Alcocer F, Wirthlin DJ, Westfall AO,Whitley D. Abdominal aortic aneurysms in ‘highrisk’surgical patients – comparison of open andendovascular repair. Ann Surg 2003;237:623–9.267. Kohsaka S, Dougherty K, Lee VV, Mitchell JH,Mortazavi A, Strickman N, et al. Long-term survivalof endovascular or surgical repair of abdominalaortic aneurysms. Circulation 2006;114:395.268. Kovacs MF, Katzen BT, Benenati JF, Zemel G,Powell A, Becker GJ. Pre-operative renal function:an independent predictor of long-term survivalfollowing endovascular repair of AAA. Circulation2003;108:IV–335.269. Larzon T, Lindgren R, Norgren L. Endovasculartreatment of ruptured abdominal aorticaneurysms: a shift of the paradigm? J Endovasc Ther2005;12:548–55.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48270. Larzon T, Lindgren R, Norgren L. [Endovasculartreatment possible in ruptured abdominal aorticaneurysm]. Lakartidningen 2005;102:1320–2.271. Laukontaus SJ, Lepantalo M, Hynninen M,Kantonen I, Pettila V. Prediction of survival after48-h of intensive care following open surgical repairof ruptured abdominal aortic aneurysm. Eur J VascEndovasc Surg 2005;30:509–15.272. Laukontaus SJ, Pettila V, Kantonen I, Salo JA,Ohinmaa A, Lepantalo M. Utility of surgery forruptured abdominal aortic aneurysm. Ann Vasc Surg2006;20:42–8.273. Lazarides MK, Arvanitis DP, Drista H, StaramosDN, Dayantas JN. POSSUM and APACHE II scoresdo not predict the outcome of ruptured infrarenalaortic aneurysms. Ann Vasc Surg 1997;11:155–8.274. Leo E, Biancari F, Kechagias A, Ylonen K, RainioP, Romsi P, et al. Outcome after emergency repairof symptomatic, unruptured abdominal aorticaneurysm: results in 42 patients and review of theliterature. Scand Cardiovasc J 2005;39:91–5.275. Leo E, Biancari F, Hanhela R, Karlqvist K, RomsiP, Ylonen K, et al. Baseline oxygen deliveryis associated with an increased risk of severepostoperative complications after elective openrepair of abdominal aortic aneurysm. J CardiovascSurg 2005;46:279–84.276. Leo E, Biancari F, Nesi F, Pogany G, BartolucciR, De Pasquale F, et al. Risk-scoring methods inpredicting the immediate outcome after emergencyopen repair of ruptured abdominal aorticaneurysm. Am J Surg 2006;192:19–23.277. Lo A, Adams D. Ruptured abdominal aorticaneurysms: risk factors for mortality afteremergency repair. N Z Med J 2004;117:U1100.278. Manis G, Feuerman M, Hines GL. Open aneurysmrepair in elderly patients not candidates forendovascular repair (EVAR): comparison withpatients undergoing EVAR or preferential openrepair. Vasc Endovascular Surg 2006;40:95–101.279. Masuda EM, Caps MT, Singh N, Yorita K, SchneiderPA, Sato DT, et al. Effect of ethnicity on access anddevice complications during endovascular aneurysmrepair. J Vasc Surg 2004;40:24–9.280. Matsumura JS, Moore WS. Clinical consequencesof periprosthetic leak after endovascular repairof abdominal aortic aneurysm. EndovascularTechnologies Investigators. J Vasc Surg 1998;27:606–13.281. Mehta M, Roddy SP, Darling IRC, OzsvathKJ, Kreienberg PB, Paty PSK, et al. Infrarenal© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.abdominal aortic aneurysm repair via endovascularversus open retroperitoneal approach. Ann Vasc Surg2005;19:374–8.282. Moore R, Nutley M, Cina CS, Motamedi M, Faris P,Abuznadah W. Improved survival after introductionof an emergency endovascular therapy protocol forruptured abdominal aortic aneurysms. J Vasc Surg2007;45:443–50.283. Neary WD, Crow P, Foy C, Prytherch D, HeatherBP, Earnshaw JJ. Comparison of POSSUM scoringand the Hardman Index in selection of patients forrepair of ruptured abdominal aortic aneurysm. Br JSurg 2003;90:421–5.284. Pamler R. Is standard surgical repair better thanendovascular repair of AAA? A statistical analysison perioperative complications. In Abstracts of the37th Congress of the European Society for SurgicalResearch, Szeged, Hungary, 2002. pp. 91–4.285. Parlani G, Verzini F, Zannetti S, De Rango P,Lenti M, Lupattelli L, et al. Does gender influenceoutcome of AAA endoluminal repair? Eur J VascEndovasc Surg 2003;26:69–73.286. Parmer SS, Fairman RM, Karmacharya J, CarpenterJP, Velazquez OC, Woo EY. A comparison of renalfunction between open and endovascular aneurysmrepair in patients with baseline chronic renalinsufficiency. J Vasc Surg 2006;44:706–11.287. Peppelenbosch N, Geelkerken RH, Soong C, CaoP, Steinmetz OK, Teijink JAW, et al. Endografttreatment of ruptured abdominal aorticaneurysms using the Talent aortouniiliac system:an international multicenter study. J Vasc Surg2006;43:1111–23.288. Polterauer P, Prusa AM, Wolff KS. XXXII.4The availability of endovascular aneurysmrepairs reduces overall mortality rates fortreating abdominal aortic aneurysms. Vascular2005;13(Suppl.1):S155.289. Prytherch DR, Sutton GL, Boyle JR. PortsmouthPOSSUM models for abdominal aortic aneurysmsurgery. Br J Surg 2001;88:958–63.290. Robbins M, Kritpracha B, Beebe HG, Criado FJ,Daoud Y, Comerota AJ. Suprarenal endograftfixation avoids adverse outcomes associated withaortic neck angulation. Ann Vasc Surg 2005;19:172–7.291. Rockman CB, Lamparello PJ, Adelman MA,Jacobowitz GR, Therff S, Gagne PJ, et al. Aneurysmmorphology as a predictor of endoleak followingendovascular aortic aneurysm repair: do smalleraneurysm have better outcomes? Ann Vasc Surg2002;16:644–51.159

References292. Sampaio SM, Panneton JM, Mozes GI, Andrews JC,Noel AA, Karla M, et al. Endovascular abdominalaortic aneurysm repair: does gender matter? AnnVasc Surg 2004;18:653–60.293. Sbarigia E, Speziale F, Ducasse E, Giannoni MF,Ruggiero M, Palmieri A, et al. What is the bestmanagement for abdominal aortic aneurysm inpatients at high surgical risk? A single-center review.Int Angiol 2005;24:70–4.294. Schouten O, Bax JJ, Poldermans D. Endovascularrepair of abdominal aortic aneurysm. N Engl J Med2005;353:1181–2.295. Schouten O, Dunkelgrun M, Feringa HHH, KokNFM, Vidakovic R, Bax JJ, et al. Myocardialdamage in high-risk patients undergoing electiveendovascular or open infrarenal abdominalaortic aneurysm repair. Eur J Vasc Endovasc Surg2007;33:544–9.296. Shames ML, Sanchez LA, Rubin BG, Choi ET,Geraghty PJ, Flye MW, et al. Delayed complicationsafter endovascular AAA repair in women. J EndovascTher 2003;10:10–15.297. Sharif MA, Arya N, Soong CV, Lau LL, O’DonnellME, Blair PH, et al. Validity of the Hardman indexto predict outcome in ruptured abdominal aorticaneurysm. Ann Vasc Surg 2007;21:34–8.298. Shuhaiber JH, Hankins M, Robless P, WhiteheadSM. Comparison of POSSUM with P-POSSUM forprediction of mortality in infrarenal abdominalaortic aneurysm repair. Ann Vasc Surg 2002;16:736–41.299. Silverberg D, Baril DT, Ellozy SH, CarroccioA, Greyrose SE, Lookstein RA, et al. An 8-yearexperience with type II endoleaks: natural historysuggests selective intervention is a safe approach. JVasc Surg 2006;44:453–9.300. Slovut DP, Ofstein LC, Bacharach JM. EndoluminalAAA repair using intravascular ultrasound for graftplanning and deployment: a 2-year communitybasedexperience. J Endovasc Ther 2003;10:463–75.301. Tambyraja AL, Fraser SCA, Murie JA, ChalmersRTA. Value of the Glasgow Aneurysm Score andHardman Score in predicting outcome afterruptured abdominal aortic aneurysm repair. Br JSurg 2004;91:110.302. Tambyraja AL, Fraser SCA, Murie JA, ChalmersRTA. Validity of the Glasgow Aneurysm Score andthe Hardman Index in predicting outcome afterruptured abdominal aortic aneurysm repair. Br JSurg 2005;92:570–3.303. Teufelsbauer H, Prusa AM, Wolff K, Polterauer P,Nanobashvili J, Prager M, et al. Endovascular stentgrafting versus open surgical operation in patientswith infrarenal aortic aneurysms: a propensity scoreadjustedanalysis. Circulation 2002;106:782–7.304. Timaran CH, Ohki T, Rhee SJ, Veith FJ, GargiuloNJ, III, Toriumi H, et al. Predicting aneurysmenlargement in patients with persistent type IIendoleaks. J Vasc Surg 2004;39:1157–62.305. Timaran CH, Lipsitz EC, Veith FJ, Chuter T,Greenberg RK, Ohki T, et al. Endovascular aorticaneurysm repair with the Zenith endograft inpatients with ectatic iliac arteries. Ann Vasc Surg2005;19:161–6.306. Torsello G, Osada N, Florek HJ, Horsch S,Kortmann H, Luska G, et al. Long-term outcomeafter Talent endograft implantation for aneurysmsof the abdominal aorta: a multicenter retrospectivestudy. J Vasc Surg 2006;43:277–84.307. Treska V, Cechura M, Molacek J, Certik B, PecenL. Rupture of abdominal aortic aneurysm (RAAA)– predictors of the early postoperative mortality.Zentralbl Chir 2003;128:557–60.308. Verzini F, Barzi F, Maselli A, Caporali S, Lenti M,Zannetti S, et al. Predictive factors for early successof endovascular abdominal aortic aneurysm repair.Ann Vasc Surg 2000;14:318–23.309. Verzini F, Cao P, Zannetti S, Parlani G, De RangoP, Maselli A, et al. Outcome of abdominal aorticendografting in high-risk patients: a 4-year singlecenterstudy. J Endovasc Ther 2002;9:736–42.310. Vogel TR, Nackman GB, Crowley JG, BuenoMM, Banavage A, Odroniec K, et al. Factorsimpacting functional health and resource utilizationfollowing abdominal aortic aneurysm repair byopen and endovascular techniques. Ann Vasc Surg2005;19:641–7.311. Walker SR, Macierewicz J, MacSweeney ST, GregsonRH, Whitaker SC, Wenham PW, et al. Mortality ratesfollowing endovascular repair of abdominal aorticaneurysms. J Endovasc Surg 1999;6:233–8.312. Wolf YG, Arko FR, Hill BB, Olcott IC, Harris EJ, Jr,Fogarty TJ, et al. Gender differences in endovascularabdominal aortic aneurysm repair with the AneuRxstent graft. J Vasc Surg 2002;35:882–6.313. Yii MK. Comparative audit of abdominal aorticaneurysm repairs using POSSUM scores. Asian JSurg 2003;26:149–53.160

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48314. Zeebregts CJ, Geelkerken RH, van der Palen J,Huisman AB, de Smit P, van Det RJ. Outcome ofabdominal aortic aneurysm repair in the era ofendovascular treatment. Br J Surg 2004;91:563–8.315. Kind P, Hardman G, Macran S. Population normsfor EQ-5D. Discussion Paper 172. York: Centre forHealth Economics; 1999.161© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Appendix 1Literature search strategiesLiterature searches were carried out to identifysystematic reviews, guidelines, ongoingtrials, RCTs, risk modelling studies, reports fromspecified EVAR registries and economic studies.Systematic reviewsTo identify systematic reviews the following weresearched:Cochrane Database of SystematicReviews, DARE, HTA databaseVia Cochrane Library – 2007 Issue 4Searched 17 September 2007Search strategy:#1 (evar):ti,ab,kw or “endovascular stent*”:ti,ab,kwor “endovascular repair*”:ti,ab,kw or“endovascular treat*”:ti,ab,kw or “endovascularsurg*”:ti,ab,kw#2 “endovascular aneurysm repair*”#3 “endoluminal stent*”:ti,ab,kw or “endoluminalrepair*”:ti,ab,kw or “endoluminaltreat*”:ti,ab,kw or “endoluminal surg*”:ti,ab,kw#4 (#1 OR #2 OR #3)#5 MeSH descriptor Aortic Aneurysm, Abdominalexplode all trees#6 (AAA):ti,ab,kw or “abdominal aorticaneurysm*”:ti,ab,kw or “abdominalaneurysm*”:ti,ab,kw#7 (#5 OR #6)#8 (#4 AND #7)GuidelinesTo identify guidelines the following databases andweb pages were searched/scanned:TRIP databasewww.tripdatabase.com/index.htmlSearched 11 September 2007NLH National Library of Guidelineswww.library.nhs.uk/guidelinesFinder/Searched 11 September 2007National Guideline Clearinghousewww.guideline.gov/Searched 29 October 2007© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.NICE web pageswww.nice.org.uk/Searched 29 October 2007RCTs, risk studies andregistry dataThe following bibliographic databases weresearched to identify RCTs (2005–7), risk studiesand papers based on registry data:BIOSIS Previews ®Via DialogSearched 18 September 2007Search strategy:S1 131 EVAR/TI,AB,DES2 641 ENDOVASCULAR(W)STENT?/TI,AB,DES3 506 ENDOVASCULAR(W)REPAIR?/TI,AB,DES4 1078 ENDOVASCULAR(W)TREAT?/TI,AB,DES5 169 ENDOVASCULAR(W)SURG?/TI,AB,DES6 166 ENDOVASCULAR(W)ANEURYSM(W)REPAIR?/TI,AB,DES7 155 ENDOLUMINAL(W)STENT?/TI,AB,DES8 49 ENDOLUMINAL(W)REPAIR?/TI,AB,DES9 51 ENDOLUMINAL(W)TREAT?/TI,AB,DES10 5 ENDOLUMINAL(W)SURG?/TI,AB,DES11 2497 S1:S10S12 2931 AAA/TI,AB,DES13 2767 ABDOMINAL(W)AORTIC(W)ANEURYSM?/TI,AB,DES14 215 ABDOMINAL(W)ANEURYSM?/TI,AB,DES15 4836 S12:S14S16 544 S11 AND S15S17 3 AAA(W)ENDOGRAFT?/TI,AB,DES18 546 S16 OR S17S19 44179 RANDOM?/TIS20 45754 TRIAL/TIS21 36106 DOUBLE(W)BLIND?/ABS22 3073 SINGLE(W)BLIND?/ABS23 99005 S19:S22S24 20 S18 AND S23S25 6 S24/2005:2007S26 11 (EUROSTAR(2W)(REGISTRY ORREGISTER OR PROJECT OR DATABASE ORDATA OR COLLABORAT? OR GROUP?))/TI,ABS27 16 (EUROSTAR AND (EVAR OR STENT? ORGRAFT? OR ANEURYSM?))/TI,AB163

Appendix 1164S28 16 RETA/TI,ABS29 0 REGISTRY(2W)ENDOVASCULAR(W)TREATMENT(2W)ANEURYSMS/TI,ABS30 1 NATIONAL(W)VASCULAR(W)DATABASE/TI,ABS31 33 S26:S30S32 2 (HARDMAN(W)(INDEX OR SCORE? ORSCORING OR MEASURE?))/TI,ABS33 2 GLASGOW(W)ANEURYSM(W)SCORE?/TI,ABS34 22 (POSSUM(W)(INDEX OR SCORE? ORSCORING OR MEASURE?))/TI,ABS35 1 MODIFIED(W)LEIDEN(W)SCORE/ABS36 1 MODIFIED(W)COMORBIDITY(W)SEVERITY(W)SCORE/ABS37 26 S32:S36S38 212323 (RISK? OR MORTALITY ORSURVIVAL OR DEATH)/TIS39 131 EVAR/TI,AB,DES40 641 ENDOVASCULAR(W)STENT?/TI,AB,DES41 506 ENDOVASCULAR(W)REPAIR?/TI,AB,DES42 1078 ENDOVASCULAR(W)TREAT?/TI,AB,DES43 169 ENDOVASCULAR(W)SURG?/TI,AB,DES44 166 ENDOVASCULAR(W)ANEURYSM(W)REPAIR?/TI,AB,DES45 155 ENDOLUMINAL(W)STENT?/TI,AB,DES46 49 ENDOLUMINAL(W)REPAIR?/TI,AB,DES47 51 ENDOLUMINAL(W)TREAT?/TI,AB,DES48 5 ENDOLUMINAL(W)SURG?/TI,AB,DES49 3 AAA(W)ENDOGRAFT?/TI,ABS50 2499 S39:S49S51 71 S38 AND S50S52 134 S25 OR S31 OR S37 OR S51S53 1453415 (RAT OR RATS OR MOUSE ORMICE OR HAMSTER OR HAMSTERS ORANIMAL OR ANIMALS OR DOG OR DOGSOR CAT OR CATS OR BOVINE OR SHEEPOR FLY OR FLIES OR FISH OR FISHES ORBAT OR BATS OR BEE OR BEES OR GRASSOR GRASSES OR FOSSIL OR FOSSILS ORLICHEN OR LICHENS OR MUSHROOMOR MUSHROOMS)/AB,TIS54 129 S52 NOT S53S55 534304 ANIMALS56 4001770 HUMANS57 413787 S55 NOT (S55 AND S56)S58 129 S54 NOT S57CINAHL – Cumulative Index to Nursingand Allied Health LiteratureVia Ovid – 1982 to August Week 5 2007Searched 10 September 2007Search strategy:1. EVAR.ti,ab. (25)2. endovascular stent$.ti,ab. (83)3. endovascular repair$.ti,ab. (93)4. endovascular treat$.ti,ab. (94)5. endovascular surg$.ti,ab. (17)6. endovascular aneurysm repair$.ti,ab. (24)7. endoluminal stent$.ti,ab. (12)8. endoluminal repair$.ti,ab. (6)9. endoluminal treat$.ti,ab. (3)10. endoluminal surg$.ti,ab. (0)11. or/1–10 (296)12. AAA$.ti,ab. (382)13. exp aortic aneurysm/(995)14. abdominal aortic aneurysm$.ti,ab. (390)15. abdominal aneurysm$.ti,ab. (11)16. or/12–15 (1265)17. 11 and 16 (144)18. AAA endograft$.ti,ab. (3)19. 17 or 18 (147)20. vascular surgery/(477)21. 20 and 16 (119)22. 19 or 21 (197)23. exp clinical trials/(47023)24. clinical trial.pt. (22538)25. (clinic$adj trial$).tw. (11002)26. ((singl$or doubl$or trebl$or tripl$) adj(blind$3 or mask$3)).tw. (6495)27. randomi?ed control$trial$.tw. (9627)28. random assignment/(16139)29. random$allocat$.tw. (1061)30. placebo$.tw. (9144)31. placebos/(3742)32. quantitative studies/(3400)33. allocat$random$.tw. (62)34. or/23–33 (65834)35. 22 and 34 (17)36. (EUROSTAR adj2 (registry or register orproject or database or data or collaborat$orgroup$)).ti,ab. (3)37. (EUROSTAR and (evar or stent$or graft$oraneurysm$)).ti,ab. (3)38. reta.ti,ab. (2)39. registry of endovascular treatment ofaneurysms.ti,ab. (0)40. national vascular database.ti,ab. (0)41. 36 or 37 or 38 or 39 or 40 (5)42. (Hardman adj (index or score$or scoring ormeasure$)).ti,ab. (0)43. Glasgow aneurysm score$.ti,ab. (0)44. (POSSUM adj (index or score$or scoring ormeasure$)).ti,ab. (4)45. Modified Leiden Score.ti,ab. (0)46. Modified Comorbidity Severity Score.ti,ab. (0)47. 42 or 43 or 44 or 45 or 46 (4)48. risk assessment/(9540)49. risk factors/(21665)50. survival analysis/(4131)51. mortality/(5604)

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 4852. roc curve/(1418)53. “Sensitivity and Specificity”/(10462)54. (risk$or mortality or survival or death).ti.(47061)55. (roc curve$or sensitivity or specificity).ab.(10517)56. 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55(89143)57. EVAR.ti,ab. (25)58. endovascular stent$.ti,ab. (83)59. endovascular repair$.ti,ab. (93)60. endovascular treat$.ti,ab. (94)61. endovascular surg$.ti,ab. (17)62. endovascular aneurysm repair$.ti,ab. (24)63. endoluminal stent$.ti,ab. (12)64. endoluminal repair$.ti,ab. (6)65. endoluminal treat$.ti,ab. (3)66. endoluminal surg$.ti,ab. (0)67. AAA endograft$.ti,ab. (3)68. vascular surgery/(477)69. or/57–68 (682)70. 56 and 69 (91)71. 35 or 41 or 47 or 70 (109)72. from 71 keep 1–109 (109)Cochrane Central Registerof Controlled TrialsVia Cochrane Library – 2007 Issue 4Searched 11 September 2007Search strategy:#1 (evar):ti,ab,kw or “endovascularstent*”:ti,ab,kw or “endovascularrepair*”:ti,ab,kw or “endovasculartreat*”:ti,ab,kw or “endovascularsurg*”:ti,ab,kw in Clinical Trials (52)#2 “endovascular aneurysm repair*”:ti,ab,kwor “endoluminal stent*”:ti,ab,kw or“endoluminal repair*”:ti,ab,kw or“endoluminal treat*”:ti,ab,kw or “endoluminalsurg*”:ti,ab,kw in Clinical Trials (21)#3 (#1 OR #2) (84)#4 (AAA*):ti,ab,kw or “abdominal aorticaneurysm*”:ti,ab,kw or “abdominalaneurysm*”:ti,ab,kw in Clinical Trials (507)#5 MeSH descriptor Aortic Aneurysm,Abdominal explode all trees (395)#6 (#4 OR #5) (728)#7 (#3 AND #6) (60)#8 “AAA endograft*”:ti,ab,kw in Clinical Trials (0)#9 (#7 or #8) (60)#10 MeSH descriptor Vascular Surgical Proceduresexplode all trees (4141)#11 (#6 and #10) (141)#12 (#9 or #11) (161)#13 (#12), from 2005 to 2007© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.EMBASEVia Ovid – 1980 to 2007 Week 35Searched 6 September 2007Search strategy:1. EVAR.ti,ab. (422)2. endovascular stent$.ti,ab. (1345)3. endovascular repair$.ti,ab. (1373)4. endovascular treat$.ti,ab. (2990)5. endovascular surg$.ti,ab. (385)6. endovascular aneurysm repair$.ti,ab. (438)7. endoluminal stent$.ti,ab. (280)8. endoluminal repair$.ti,ab. (171)9. endoluminal treat$.ti,ab. (140)10. endoluminal surg$.ti,ab. (24)11. or/1–10 (6306)12. AAA$.ti,ab. (5101)13. exp aorta aneurysm/(15874)14. abdominal aortic aneurysm$.ti,ab. (6740)15. abdominal aneurysm$.ti,ab. (515)16. or/12–15 (18921)17. 11 and 16 (2246)18. AAA endograft$.ti,ab. (14)19. 17 or 18 (2254)20. vascular surgery/(10955)21. 20 and 16 (1022)22. 19 or 21 (3162)23. clinical trial/(469549)24. randomized controlled trial/(146648)25. randomization/(23723)26. single blind procedure/(6886)27. double blind procedure/(65699)28. crossover procedure/(19208)29. placebo/(103122)30. randomi?ed controlled trial$.tw. (25624)31. rct.tw. (1969)32. random allocation.tw. (584)33. randomly allocated.tw. (9232)34. allocated randomly.tw. (1293)35. (allocated adj2 random).tw. (547)36. single blind$.tw. (6783)37. double blind$.tw. (78511)38. ((treble or triple) adj blind$).tw. (122)39. placebo$.tw. (100415)40. prospective study/(68159)41. or/23–40 (619632)42. case study/(5041)43. case report.tw. (106789)44. abstract report/or letter/(443249)45. or/42–44 (553223)46. 41 not 45 (598087)47. 22 and 46 (390)48. limit 47 to yr=“2005 – 2007” (134)49. (EUROSTAR adj2 (registry or register orproject or database or data or collaborat$orgroup$)).ti,ab. (50)165

Appendix 116650. (EUROSTAR and (evar or stent$or graft$oraneurysm$)).ti,ab. (62)51. reta.ti,ab. (11)52. registry of endovascular treatment ofaneurysms.ti,ab. (1)53. national vascular database.ti,ab. (7)54. 49 or 50 or 51 or 52 or 53 (80)55. (Hardman adj (index or score$or scoring ormeasure$)).ti,ab. (9)56. Glasgow aneurysm score$.ti,ab. (19)57. (POSSUM adj (index or score$or scoring ormeasure$)).ti,ab. (86)58. Modified Leiden Score.ti,ab. (2)59. Modified Comorbidity Severity Score.ti,ab. (1)60. 55 or 56 or 57 or 58 or 59 (108)61. risk assessment/(151661)62. risk factor/(205117)63. survival rate/(48556)64. survival time/(24668)65. overall survival/(3310)66. survival/(55421)67. mortality/(149265)68. roc curve/(1438)69. “Sensitivity and Specificity”/(37627)70. (risk$or mortality or survival or death).ti.(238237)71. (roc curve$or sensitivity or specificity).ab.(359551)72. 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or69 or 70 or 71 (1014439)73. EVAR.ti,ab. (422)74. endovascular stent$.ti,ab. (1345)75. endovascular repair$.ti,ab. (1373)76. endovascular treat$.ti,ab. (2990)77. endovascular surg$.ti,ab. (385)78. endovascular aneurysm repair$.ti,ab. (438)79. endoluminal stent$.ti,ab. (280)80. endoluminal repair$.ti,ab. (171)81. endoluminal treat$.ti,ab. (140)82. endoluminal surg$.ti,ab. (24)83. AAA endograft$.ti,ab. (14)84. or/73–83 (6314)85. 72 and 84 (1297)86. 48 or 54 or 60 or 85 (1505)87. from 86 keep 1–1505 (1505)ISI ProceedingsVia Web of ScienceSearched 18 September 2007Search strategy:TS=evar (140)TS=(endovascular SAME (stent* OR repair* ORtreat* OR surger*)) (1639)TS=(endoluminal SAME (stent* OR repair* ORtreat* OR surger*)) (241)#1 or #2 or #3 (1804)TS=(AAA OR abdominal aortic aneurysm* ORabdominal aneurysm*) (2273)#5 or #4 (619)MEDLINE ®Via Ovid – 1950 to August Week 5 2007Searched 6 September 2007Search strategy:1. EVAR.ti,ab. (404)2. endovascular stent$.ti,ab. (1354)3. endovascular repair$.ti,ab. (1394)4. endovascular treat$.ti,ab. (2595)5. endovascular surg$.ti,ab. (374)6. endovascular aneurysm repair$.ti,ab. (417)7. endoluminal stent$.ti,ab. (286)8. endoluminal repair$.ti,ab. (169)9. endoluminal treat$.ti,ab. (126)10. endoluminal surg$.ti,ab. (20)11. or/1–10 (5920)12. AAA$.ti,ab. (5868)13. exp aortic aneurysm, abdominal/(8427)14. abdominal aortic aneurysm$.ti,ab. (7979)15. abdominal aneurysm$.ti,ab. (713)16. or/12–15 (14579)17. 11 and 16 (1838)18. AAA endograft$.ti,ab. (13)19. 17 or 18 (1846)20. vascular surgical procedures/(16153)21. 20 and 16 (1121)22. 19 or 21 (2645)23. RANDOMIZED CONTROLLED TRIAL.pt.(242026)24. CONTROLLED CLINICAL TRIAL.pt. (76175)25. RANDOMIZED CONTROLLED TRIALS.sh.(50846)26. RANDOM ALLOCATION.sh. (58962)27. DOUBLE BLIND METHOD.sh. (93291)28. SINGLE BLIND METHOD.sh. (11312)29. or/23–28 (410206)30. (ANIMALS not HUMANS).sh. (3178675)31. 29 not 30 (384781)32. CLINICAL TRIAL.pt. (441091)33. exp CLINICAL TRIALS/(196388)34. (clin$adj25 trial$).ti,ab. (135407)35. ((singl$or doubl$or trebl$or tripl$) adj25(blind$or mask$)).ti,ab. (92729)36. PLACEBOS.sh. (26592)37. placebo$.ti,ab. (104970)38. random$.ti,ab. (385021)39. RESEARCH DESIGN.sh. (49242)40. or/32–39 (870519)41. 40 not 30 (807906)42. 41 not 31 (442725)

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 4843. 31 or 42 (827506)44. 22 and 43 (379)45. limit 44 to yr=“2005 – 2007” (126)46. (EUROSTAR adj2 (registry or register orproject or database or data or collaborat$orgroup$)).ti,ab. (50)47. (EUROSTAR and (evar or stent$or graft$oraneurysm$)).ti,ab. (60)48. reta.ti,ab. (12)49. registry of endovascular treatment ofaneurysms.ti,ab. (1)50. national vascular database.ti,ab. (5)51. 46 or 47 or 48 or 49 or 50 (77)52. (Hardman adj (index or score$or scoring ormeasure$)).ti,ab. (11)53. Glasgow aneurysm score$.ti,ab. (21)54. (POSSUM adj (index or score$or scoring ormeasure$)).ti,ab. (85)55. Modified Leiden Score.ti,ab. (2)56. Modified Comorbidity Severity Score.ti,ab. (1)57. 52 or 53 or 54 or 55 or 56 (109)58. risk assessment/(81774)59. risk factors/(326347)60. survival analysis/(63460)61. mortality/(27549)62. roc curve/(11339)63. “Sensitivity and Specificity”/(171061)64. (risk$or mortality or survival or death).ti.(313939)65. (roc curve$or sensitivity or specificity).ab.(419309)66. 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65(1155607)67. EVAR.ti,ab. (404)68. endovascular stent$.ti,ab. (1354)69. endovascular repair$.ti,ab. (1394)70. endovascular treat$.ti,ab. (2595)71. endovascular surg$.ti,ab. (374)72. endovascular aneurysm repair$.ti,ab. (417)73. endoluminal stent$.ti,ab. (286)74. endoluminal repair$.ti,ab. (169)75. endoluminal treat$.ti,ab. (126)76. endoluminal surg$.ti,ab. (20)77. AAA endograft$.ti,ab. (13)78. vascular surgical procedures/(16153)79. or/67–78 (21316)80. 66 and 79 (2246)81. 45 or 51 or 57 or 80 (2470)82. from 81 keep 1–2470 (2470)MEDLINE ® In-Process & OtherNon-Indexed CitationsVia Ovid© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.Searched 7 September 2007Search strategy:1. EVAR.ti,ab. (37)2. endovascular stent$.ti,ab. (66)3. endovascular repair$.ti,ab. (74)4. endovascular treat$.ti,ab. (127)5. endovascular surg$.ti,ab. (15)6. endovascular aneurysm repair$.ti,ab. (33)7. endoluminal stent$.ti,ab. (9)8. endoluminal repair$.ti,ab. (1)9. endoluminal treat$.ti,ab. (4)10. endoluminal surg$.ti,ab. (1)11. or/1–10 (291)12. AAA$.ti,ab. (181)13. abdominal aortic aneurysm$.ti,ab. (185)14. abdominal aneurysm$.ti,ab. (12)15. AAA endograft$.ti,ab. (0)16. or/13–15 (189)17. 11 and 16 (67)18. RANDOMIZED CONTROLLED TRIAL.pt.(373)19. CONTROLLED CLINICAL TRIAL.pt. (22)20. CLINICAL TRIAL.pt. (354)21. (clin$adj25 trial$).ti,ab. (4733)22. ((singl$or doubl$or trebl$or tripl$) adj25(blind$or mask$)).ti,ab. (1686)23. placebo$.ti,ab. (2174)24. random$.ti,ab. (17378)25. or/18–24 (21406)26. 17 and 25 (8)27. (EUROSTAR adj2 (registry or register orproject or database or data or collaborat$orgroup$)).ti,ab. (1)28. (EUROSTAR and (evar or stent$or graft$oraneurysm$)).ti,ab. (1)29. reta.ti,ab. (0)30. registry of endovascular treatment ofaneurysms.ti,ab. (0)31. national vascular database.ti,ab. (0)32. 27 or 28 or 29 or 30 or 31 (1)33. (Hardman adj (index or score$or scoring ormeasure$)).ti,ab. (2)34. Glasgow aneurysm score$.ti,ab. (1)35. (POSSUM adj (index or score$or scoring ormeasure$)).ti,ab. (2)36. Modified Leiden Score.ti,ab. (0)37. Modified Comorbidity Severity Score.ti,ab. (0)38. 33 or 34 or 35 or 36 or 37 (4)39. (risk$or mortality or survival or death).ti.(8672)40. (roc curve$or sensitivity or specificity).ab.(12211)41. 39 or 40 (20606)42. EVAR.ti,ab. (37)43. endovascular stent$.ti,ab. (66)167

Appendix 116844. endovascular repair$.ti,ab. (74)45. endovascular treat$.ti,ab. (127)46. endovascular surg$.ti,ab. (15)47. endovascular aneurysm repair$.ti,ab. (33)48. endoluminal stent$.ti,ab. (9)49. endoluminal repair$.ti,ab. (1)50. endoluminal treat$.ti,ab. (4)51. endoluminal surg$.ti,ab. (1)52. AAA endograft$.ti,ab. (0)53. or/42–52 (291)54. 26 or 32 or 38 or 53 (295)55. from 54 keep 1–295 (295)Science Citation IndexVia Web of ScienceSearched 18 September 2007Three separate searches carried out to identifyRCTs, specified registry reports, risk modellingstudies:RCT search strategy (limited to 2005–7)TS=EVAR (253)TS=(endovascular SAME (stent* OR repair* ORtreat* OR surger*)) (2965)TS=(endoluminal SAME (stent* OR repair* ORtreat* OR surger*)) (252)TS=(AAA OR abdominal aortic aneurysm* ORabdominal aneurysm*) (2954)#3 or #2 or #1 (3143)#5 AND #4 (798)TS=(RANDOMIZED CONTROLLED-TRIAL orRANDOMISED CONTROLLED-TRIAL) (21120)TI=(trial* or random*) (40781)#8 or #7 (55388)#9 and #6 (121)Registry reports searchstrategy, no date limitsTS=(EUROSTAR SAME (registry OR register ORproject OR database OR data OR collaborat* ORgroup*)) (55)TS=(EUROSTAR SAME (evar OR stent* OR graft*OR aneurysm*)) (41)TS=(reta OR “registry of endovascular treatmentof aneurysms” OR “national vascular database”)(38)TS=(hardman SAME (index OR score* OR scoringOR measure*)) (12)TS=(“glasgow aneurysm score*” OR “modifiedleiden score” OR “modified comorbidity severityscore”) (23)TS=(possum same (index OR score* OR scoringOR measure*)) (190)#6 OR #5 OR #4 OR #3 OR #2 OR #1 (313)Risk modelling studies searchstrategy, no date limitsTS=EVARTS=(endovascular SAME (stent* OR repair* ORtreat* OR surger*))TS=(endoluminal SAME (stent* OR repair* ORtreat* OR surger*))TS=(“AAA endograft*”)#4 OR #3 OR #2 OR #1TI=(risk* OR mortality OR survival OR death)#6 and #5 (248 papers)Zetoc ConferencesSearched 18 September 2007Series of searches carried out using terms: EVAR,endovascular stents, endovascular repair/treatment/surgery AND aneurysm (170 papers identified)Ongoing studiesTo identify any ongoing studies the following weresearched:Clinicaltrials.govhttp://clinicaltrials.gov/Searched 11 September 2007Search terms: aneurysm AND endovascular (nodate limits)Results: 23Current Controlled Trialswww.controlled-trials.com/Searched 11 September 2007Search terms: aneurysm AND endovascular (nodate limits)Results: 45National Research Register2007 Issue 3Searched 11 September 2007Search stategy:#1 evar (67)#2 (endovascular next stent*) (38)#3 (endovascular next repair*) (49)#4 (endovascular next treat*) (37)#5 (endovascular next surger*) (16)#6 (endoluminal next stent*) (2)#7 (endoluminal next repair*) (6)#8 (endoluminal next treat*) (0)#9 (endoluminal next surger*) (0)#10 (endovascular next aneurysm next repair*)(60)#11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or#8 or #9 or #10 (180)#12 aaa* (104)

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48#13 (abdominal next aortic next aneurysm*) (196)#14 (abdominal next aneurysm*) (12)#15 AORTIC ANEURYSM ABDOMINAL explodeall trees (MeSH) (128)#16 #12 or #13 or #14 or #15 (246)#17 #11 and #16 (80)#18 (aaa next endograft*) (1)#19 (#17 or #18) (80)#20 VASCULAR SURGICAL PROCEDURESexplode tree 1 (MeSH) (483)#21 (#16 and #20) (17)#22 (#19 or #21) (83)Economics searchesEconLITVia WebSPIRSSearched 12 October 2007Search strategy:#1 EVAR in ti,ab (0 records)#2 endoluminal (0 records)#3 endovascular (0 records)#4 aaa (38 records)#5 abdominal aortic aneurysm* (5 records)#6 abdominal aneurysm* (1 records)#7 aaa endograft* (0 records)#8 vascular surgery (0 records)#9 vascular surgical procedure* (0 records)#10 (abdominal aortic aneurysm*) or (aaa) or(abdominal aneurysm*) (42 records)EMBASEVia OvidSearched 11 October 2007Search strategy:#1 Health Economics/(9545)#2 exp Economic Evaluation/(91514)#3 exp Health Care Cost/(93030)#4 exp PHARMACOECONOMICS/(48656)#5 or/1–4 (176440)#6 (econom$or cost or costs or costly orcosting or price or prices or pricing orpharmacoeconomic$).ti,ab. (206766)#7 (expenditure$not energy).ti,ab. (8791)#8 (value adj2 money).ti,ab. (390)#9 budget$.ti,ab. (8045)#10 or/6–9#11 5 or 10 (305033)#12 (metabolic adj cost).ti,ab. (356)#13 ((energy or oxygen) adj cost).ti,ab. (1607)#14 ((energy or oxygen) adj expenditure).ti,ab.(9073)#15 or/12–14 (10558)© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.#16 11 not 15 (302646)#17 editorial.pt. (198373)#18 note.pt. 9219980)#19 letter.pt. (394199)#20 or/17–19 (812552)#21 16 not 20 (261791)#22 (rat or rats or mouse or mice or hamster orhamsters or animal or animals or dogs or dogor cats or bovine or sheep).ti,ab,sh. (1900407)#23 exp animal/(18204)#24 Nonhuman/(2965844)#25 or/22–24 (3281976)#26 exp human (5941940)#27 exp human experiment/(240151)#28 26 or 27 (5942804)#29 25 not (25 and 28) (2713634)#30 21 not 29 (241038)#31 EVAR.ti,ab. (430)#32 endovascular stent$.ti,ab. (1359)#33 endovascular repair$.ti,ab. (1392)#34 endovascular treat$.ti,ab. (3038)#35 endovascular surg$.ti,ab. (388)#36 endovascular repair$.ti,ab. (442)#37 endoluminal stent$.ti,ab. (281)#38 endoluminal repair$.ti,ab. (171)#39 endoluminal treat$.ti,ab. (141)#40 endoluminal surg$.ti,ab. (24)#41 or/31–40 (6391)#42 AAA$.ti,ab. (5142)#43 exp aorta aneurysm/(15998)#44 abdominal aortic aneurysm$.ti,ab. (6795)#45 abdominal aneurysm$.ti,ab. (518)#46 or/42–45#47 41 and 46#48 AAA endograft$.ti,ab. (14)#49 47 or 48 (2282)#50 vascular surgery/(11029)#51 50 and 46 (1030)#52 49 or 51 (3196)#53 30 and 52 (138)#54 limit 53 to yr=“2006 – 2008” (24)HEEDSearched 11 October 2007Search strategy:(EVAR OR endovascular OR endoluminal) AND(AAA OR abdominal OR aneurysm OR aneurysms)(57 records retrieved)IDEASVia http://ideas.repec.org/Searched 11 October 2007Series of searches using the following terms:endovascular, aneurysm (three records retrieved)169

Appendix 1MEDLINEVia OvidSearched 11 October 2007Search strategy:#1 economics/(25182)#2 exp “costs and cost analysis”/(132702)#3 economics, dental/(1702)#4 exp “economics, hospital”/(14981)#5 economics, medical/(6910)#6 economics, nursing/(3749)#7 economics, pharmaceutical/(1842)#8 (economic$or cost or costs or costly orcosting or price or prices or pricing orpharmacoeconomic$).tw. (248787)#9 (expenditure$not energy).tw. (10815)#10 (value adj1 money).tw. (10)#11 budget$.tw. (11233)#12 or/1–11 (352654)#13 ((energy or oxygen) adj cost).ti,ab. (1938)#14 (metabolic adj cost).ti,ab. (455)#15 ((energy or oxygen) adj expenditure).ti,ab.(10439)#16 or/13–15 (12303)#17 12 not 16 (349802)#18 EVAR.ti,ab. (423)#19 endovascular stent$.ti,ab. (1374)#20 endovascular repair$.ti,ab. (1422)#21 endovascular treat$.ti,ab. (2632)#22 endovascular surg$.ti,ab. (375)#23 endovascular aneurysm repair$.ti,ab. (430)#24 endoluminal stent$.ti,ab. (286)#25 endoluminal repair$.ti,ab. (169)#26 endoluminal treat$.ti,ab. (128)#27 endoluminal surg$.ti,ab. (20)#28 or/18–27(6011)#29 AAA$.ti,ab. (5930)#30 exp aortic aneurysm, abdominal/(8526)#31 abdominal aortic aneurysm$.ti,ab. (8061)#32 abdominal aneurysm$.ti,ab.#33 or/29–32 (14725)#34 28 and 33#35 AAA endograft$.ti,ab. (13)#36 34 or 35 (1884)#37 vascular surgical procedures/(16286)#38 37 and 33 (1148)#39 36 or 38 (2702)#40 17 and 39 (134)#41 limit 40 to yr=“2006 – 2007” (27)NHS EEDVia internal CAIRS softwareSearched 10 October 2007Search strategy:S EVARS endovascular(w)stent$S endovascular(w)repair$S endovascular(w)treat$S endovascular(w)surg$S endovascular(w)aneurysm(w)repair$S endoluminal(w)stent$S endoluminal(w)repair$S endoluminal(w)treat$S endoluminal(w)surg$S S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 ORS8 OR S9 OR S10S AAAS aortic(w)aneurysm(w)abdominalS abdominal(w)aortic(w)aneurysm$S abdominal(w)aneurysmS s12 or s13 or s14 or s15S s11 and s16S AAA(w)endograft$S vascular(w)surgical(w)proceduresS s18 or s19S s17 or s20(25 records retrieved)170

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Appendix 2Quality assessmentChecklists for studies included in the systematic review of existingcost-effectiveness evidenceTABLE 75 Checklist for Patel et al. 105 – The cost-effectiveness of endovascular repair versus open surgical repair of abdominal aorticaneurysms: a decision analysis modelStudy question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ✗stated (e.g. NHS, society)Selection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓✓✓✓N/AEffectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✗11. Potential biases identified (especially if data not from ✗RCTs)12. Details of the method of synthesis or meta-analysis of ✓estimates are given (if based on an overview of a numberof effectiveness studies)Effectiveness data are drawn from a large rangeof sources and supplemented with a range ofassumptionsDetails are given, i.e. they have taken an average,but such methods are not considered suitableCosts13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✗accurately (with methodology)Large number of assumptions made regardingresource use15. Appropriate unit costs estimated (with methodology) ? Unit costs have been taken from the literatureand cost accounting system at New YorkPresbyterian Hospital16. Unit costs reported separately from resource use data ✗17. Productivity costs treated separately from other costs N/A Productivity costs are not consideredcontinued171© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 75 Checklist for Patel et al. 105 – The cost-effectiveness of endovascular repair versus open surgical repair of abdominal aorticaneurysms: a decision analysis model (continued)Study question Grade Comments18. The year and country to which unit costs apply arestated with appropriate adjustments for inflation and/orcurrency conversionBenefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✓✓✓✗Methods to value health states are given althoughthey appear inappropriateDecision modelling22. Details of any decision model used are given (e.g. decision ✓tree, Markov model)23. The choice of model used and the key input parameters ✓on which it is based are adequately detailed and justified24. All model outputs described adequately ✓/✗ Results are presented but, with the exception ofthe base case, costs and QALYs are not reportedseparately and only ICERs are reportedDiscounting25. Discount rate used for both costs and benefits ✓26. Do discount rates accord with NHS guidance? ✗ Discounted at 3% per annum rather than 3.5%Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)Stochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✗✗✓✗✗✗✓172Deterministic analysis34. The approach to sensitivity analysis is given (e.g.univariate, threshold analysis, etc.)? Not stated but both one-way and thresholdsensitivity analyses are undertaken35. The choice of variables for sensitivity analysis is justified ? They tested parameters based on their originalassumptions36. The ranges over which the variables are varied are stated ✗

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 75 Checklist for Patel et al. 105 – The cost-effectiveness of endovascular repair versus open surgical repair of abdominal aorticaneurysms: a decision analysis model (continued)Study question Grade CommentsPresentation of results37. Incremental analysis is reported using appropriate ✓decision rules38. Major outcomes are presented in a disaggregated as well ✗as an aggregated form39. Applicable to the NHS setting ✗ US basedTABLE 76 Checklist for Bosch et al. 108 – Abdominal aortic aneurysms: cost-effectiveness of elective endovascular and open surgicalrepairStudy question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ?stated (e.g. NHS, society)Selection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓/?✓✓✓N/AEffectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✗11. Potential biases identified (especially if data not from ✓RCTs)12. Details of the method of synthesis or meta-analysis of ✓estimates are given (if based on an overview of a numberof effectiveness studies)Costs13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✗accurately (with methodology)15. Appropriate unit costs estimated (with methodology) ?16. Unit costs reported separately from resource use data ✗continued173© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 76 Checklist for Bosch et al. 108 – Abdominal aortic aneurysms: cost-effectiveness of elective endovascular and open surgicalrepair (continued)Study question Grade Comments17. Productivity costs treated separately from other costs ✗ Productivity costs were included in the total costs18. The year and country to which unit costs apply arestated with appropriate adjustments for inflation and/orcurrency conversion✓ Costs in 2000 US dollarsBenefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✓✗✗Decision modelling22. Details of any decision model used are given (e.g. decision ✓ Markov modeltree, Markov model)23. The choice of model used and the key input parameters ✓on which it is based are adequately detailed and justified24. All model outputs described adequately ✓/✗ Only described adequately for the base case, allsensitivity analyses given in terms of thresholdsDiscounting25. Discount rate used for both costs and benefits ✓ Both discounted at 3%26. Do discount rates accord with NHS guidance? ✗ Discounted at 3% per annum rather than 3.5%Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)Stochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✗✗✗✗✗✗✗174Deterministic analysis34. The approach to sensitivity analysis is given (e.g.✓univariate, threshold analysis, etc.)35. The choice of variables for sensitivity analysis is justified ✓36. The ranges over which the variables are varied are stated ✓

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 76 Checklist for Bosch et al. 108 – Abdominal aortic aneurysms: cost-effectiveness of elective endovascular and open surgicalrepair (continued)Study question Grade CommentsPresentation of results37. Incremental analysis is reported using appropriate ✓decision rules38. Major outcomes are presented in a disaggregated as well ✓/✗as an aggregated form39. Applicable to the NHS setting ✗QALYs and costs are only disaggregated for thebase-case analysisTABLE 77 Checklist for Michaels et al. 107 – Cost-effectiveness of endovascular abdominal aortic aneurysm repairStudy question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ✓stated (e.g. NHS, society)NHSSelection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓✓✓✓N/AEffectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✓/✗11. Potential biases identified (especially if data not from ✗RCTs)12. Details of the method of synthesis or meta-analysis of ✗estimates are given (if based on an overview of a numberof effectiveness studies)Not discussed in this articleNot discussed in this article as most of theparameters are drawn from a NICE reviewCosts13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✓accurately (with methodology)15. Appropriate unit costs estimated (with methodology) ✓16. Unit costs reported separately from resource use data ✓17. Productivity costs treated separately from other costs ✗ This study does not consider productivity costscontinued175© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 77 Checklist for Michaels et al. 107 – Cost-effectiveness of endovascular abdominal aortic aneurysm repair (continued)Study question Grade Comments18. The year and country to which unit costs apply arestated with appropriate adjustments for inflation and/orcurrency conversionBenefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✓✓✓✓Decision modelling22. Details of any decision model used are given (e.g. decision ✓tree, Markov model)23. The choice of model used and the key input parameters ✓on which it is based are adequately detailed and justified24. All model outputs described adequately ✓Discounting25. Discount rate used for both costs and benefits ✓26. Do discount rates accord with NHS guidance? ✓Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)Stochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✗✓✓✓✓✓/✗✓Parameters are drawn from other studies andno discussion of any statistical tests conducted inthese other studies is given hereBeta distributions have been used appropriatelyfor probabilities, but normal distributions havebeen used for costs, which is inappropriate176Deterministic analysis34. The approach to sensitivity analysis is given (e.g.✓univariate, threshold analysis, etc.)35. The choice of variables for sensitivity analysis is justified ✓36. The ranges over which the variables are varied are stated ✓

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 77 Checklist for Michaels et al. 107 – Cost-effectiveness of endovascular abdominal aortic aneurysm repair (continued)Study question Grade CommentsPresentation of results37. Incremental analysis is reported using appropriatedecision rules38. Major outcomes are presented in a disaggregated as wellas an aggregated form39. Applicable to the NHS setting ✓✓✓/✗Incremental QALYs and costs are disaggregatedfrom one another, but the study does not givethe actual level of costs or QALYs for each armseparatelyTABLE 78 Checklist for Epstein et al. 106 – Modelling the long-term cost-effectiveness of endovascular or open repair for abdominal aorticaneurysmStudy question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ✓stated (e.g. NHS, society)Selection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓✓✓✓N/AEffectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✓11. Potential biases identified (especially if data not from ?RCTs)12. Details of the method of synthesis or meta-analysis of N/Aestimates are given (if based on an overview of a numberof effectiveness studies)Costs13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✓accurately (with methodology)15. Appropriate unit costs estimated (with methodology) ✓continued177© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 78 Checklist for Epstein et al. 106 – Modelling the long-term cost-effectiveness of endovascular or open repair for abdominalaortic aneurysm (continued)Study question Grade Comments16. Unit costs reported separately from resource use data ✓17. Productivity costs treated separately from other costs ✗18. The year and country to which unit costs apply are stated ✓with appropriate adjustments for inflation and/or currencyconversion2004 UK poundsBenefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✓✗✗Values are reported in paper but no informationon how they were valued is given here, althoughit is referenced to Kind 1999 315 and so is clearlyEQ-5DDecision modelling22. Details of any decision model used are given (e.g. decision ✓tree, Markov model)23. The choice of model used and the key input parameters ✓on which it is based are adequately detailed and justified24. All model outputs described adequately ✓Discounting25. Discount rate used for both costs and benefits ✓26. Do discount rates accord with NHS guidance? ✓Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)Stochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✓✓✓✓✓✗✓No discussion of probability distributions in thepaper although the model code is available on theinternet178

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 78 Checklist for Epstein et al. 106 – Modelling the long-term cost-effectiveness of endovascular or open repair for abdominalaortic aneurysm (continued)Study question Grade CommentsDeterministic analysis34. The approach to sensitivity analysis is given (e.g.✓univariate, threshold analysis, etc.)35. The choice of variables for sensitivity analysis is justified ✓36. The ranges over which the variables are varied are stated ✓Presentation of results37. Incremental analysis is reported using appropriate decisionrules38. Major outcomes are presented in a disaggregated as wellas an aggregated form39. Applicable to the NHS setting ✓✓✓/✗They have conducted scenario analysesIncremental QALYs and costs are disaggregatedfrom one another, but the study does not givethe actual level of costs or QALYs for each armseparatelyTABLE 79 Checklist for Prinssen et al. 126 – Cost-effectiveness of conventional and endovascular repair of abdominal aortic aneurysms:results of a randomized trialStudy question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ✗stated (e.g. NHS, society)Viewpoint is not stated but would appear to besocietal because of the inclusion of productivitycosts (in terms of sick leave)Selection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓✓✓✓N/AEffectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✓11. Potential biases identified (especially if data not from ✓RCTs)continued179© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 79 Checklist for Prinssen et al. 126 – Cost-effectiveness of conventional and endovascular repair of abdominal aortic aneurysms:results of a randomized trial (continued)Study question Grade Comments12. Details of the method of synthesis or meta-analysis ofestimates are given (if based on an overview of a numberof effectiveness studies)N/ACosts13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✓accurately (with methodology)15. Appropriate unit costs estimated (with methodology) ✓16. Unit costs reported separately from resource use data ✓/✗ Unit costs are reported but resource use dataare not17. Productivity costs treated separately from other costs ✓/✗ Productivity costs are given separately but arealso included in the total cost estimates18. The year and country to which unit costs apply arestated with appropriate adjustments for inflation and/orcurrency conversion✓ 2003 eurosBenefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✓✓✓Decision modelling22. Details of any decision model used are given (e.g. decision N/Atree, Markov model)23. The choice of model used and the key input parameters N/Aon which it is based are adequately detailed and justified24. All model outputs described adequately N/ADiscounting25. Discount rate used for both costs and benefits ✗ Study has only a 1-year time horizon and so evenif discounting was performed any changes wouldbe marginal26. Do discount rates accord with NHS guidance? ✗Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✓✓/✗✗Uncertainty in estimates of incremental costsand QALYs is represented by the presentationof the results of the bootstrapping on the costeffectivenessplane180

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 79 Checklist for Prinssen et al. 126 – Cost-effectiveness of conventional and endovascular repair of abdominal aortic aneurysms:results of a randomized trial (continued)Study question Grade CommentsStochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✗✗✗Deterministic analysis34. The approach to sensitivity analysis is given (e.g.✗univariate, threshold analysis, etc.)35. The choice of variables for sensitivity analysis is justified ✗36. The ranges over which the variables are varied are stated ✗Presentation of results37. Incremental analysis is reported using appropriate ✓decision rules38. Major outcomes are presented in a disaggregated as well ✗as an aggregated form39. Applicable to the NHS setting ✗TABLE 80 Checklist for Medtronic submission 127 – Endovascular aneurysm repair (EVAR) for the treatment of infra-renal abdominalaortic aneurysms (AAA)Study question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ✓stated (e.g. NHS, society)Selection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓✓✓✓N/Acontinued181© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 80 Checklist for Medtronic submission 127 – Endovascular aneurysm repair (EVAR) for the treatment of infra-renal abdominalaortic aneurysms (AAA) (continued)Study question Grade CommentsEffectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✓/✗11. Potential biases identified (especially if data not from ✓/✗RCTs)12. Details of the method of synthesis or meta-analysis of ✓estimates are given (if based on an overview of a numberof effectiveness studies)Costs13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✓accurately (with methodology)15. Appropriate unit costs estimated (with methodology) ✓16. Unit costs reported separately from resource use data ✓17. Productivity costs treated separately from other costs ✗ Study does not consider productivity costs18. The year and country to which unit costs apply are statedwith appropriate adjustments for inflation and/or currencyconversion? Costs are in UK pounds but the price year isunclear. Some of the reference costs are for2005/6 but others are from earlier datesBenefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✓✓✓Decision modelling22. Details of any decision model used are given (e.g. decision ✓tree, Markov model)23. The choice of model used and the key input parameters ✓on which it is based are adequately detailed and justified24. All model outputs described adequately ✓/✗ Costs and QALYs are not always disaggregatedDiscounting25. Discount rate used for both costs and benefits ✓26. Do discount rates accord with NHS guidance? ✓ Both costs and QALYs are discounted at a rateof 3.5%Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)✓/✗✓182

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 80 Checklist for Medtronic submission 127 – Endovascular aneurysm repair (EVAR) for the treatment of infra-renal abdominalaortic aneurysms (AAA) (continued)Study question Grade Comments29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)Stochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✓? This is unclear from the report but has beencarried out in the model✓? This is unclear from the report but has beencarried out in the model✓Deterministic analysis34. The approach to sensitivity analysis is given (e.g.✓univariate, threshold analysis, etc.)35. The choice of variables for sensitivity analysis is justified ✓36. The ranges over which the variables are varied are stated ✓Presentation of results37. Incremental analysis is reported using appropriate decisionrules38. Major outcomes are presented in a disaggregated as wellas an aggregated form39. Applicable to the NHS setting ✓✓✓/✗Univariate sensitivity analyses have beenconductedQALYs and costs have been disaggregated for thebase-case analysis, but only ICERs are reportedfor the sensitivity analysesTABLE 81 Checklist for EVAR trial participants 46 – Endovascular aneurysm repair and outcome in patients unfit for open repair ofabdominal aortic aneurysm (EVAR trial 2): randomised controlled trialStudy question Grade Comments1. Costs and effects examined ✓2. Alternatives compared ✓3. The viewpoint(s)/perspective of the analysis is clearly ✗stated (e.g. NHS, society)Viewpoint is not clearly stated, although fromreading the paper it is clear that it is NHSSelection of alternatives4. All relevant alternatives are compared (including donothing if applicable)5. The alternatives being compared are clearly described(who did what, to whom, where and how often)6. The rationale for choosing the alternative programmes orinterventions compared is statedForm of evaluation7. The choice of form of economic evaluation is justified inrelation to the questions addressed✓✓✓✗continued183© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 2TABLE 81 Checklist for EVAR trial participants 46 – Endovascular aneurysm repair and outcome in patients unfit for open repair ofabdominal aortic aneurysm (EVAR trial 2): randomised controlled trial (continued)Study question Grade Comments8. If a cost-minimisation design is chosen, have equivalentoutcomes been adequately demonstrated?✓Effectiveness data9. The source(s) of effectiveness estimates used are stated ✓(e.g. single study, selection of studies, systematic review,expert opinion)10. Effectiveness data from RCT or review of RCTs ✓11. Potential biases identified (especially if data not from ?RCTs)12. Details of the method of synthesis or meta-analysis of ✗estimates are given (if based on an overview of a numberof effectiveness studies)Costs13. All of the important and relevant resource use included ✓14. All of the important and relevant resource use measured ✓accurately (with methodology)15. Appropriate unit costs estimated (with methodology) ✓16. Unit costs reported separately from resource use data ✗17. Productivity costs treated separately from other costs ✗ Productivity costs were not considered18. The year and country to which unit costs apply arestated with appropriate adjustments for inflation and/orcurrency conversion✗Benefit measurement and valuation19. The primary outcome measure(s) for the economicevaluation are clearly stated20. Methods to value health states and other benefits arestated21. Details of the individuals from whom valuations wereobtained are given✗✓✓Decision modelling22. Details of any decision model used are given (e.g. N/Adecision tree, Markov model)23. The choice of model used and the key input parameters N/Aon which it is based are adequately detailed and justified24. All model outputs described adequately N/ADiscounting25. Discount rate used for both costs and benefits ✗ Only costs are discounted26. Do discount rates accord with NHS guidance? ? Discount rate is not stated184Allowance for uncertaintyStochastic analysis of patient-level data27. Details of statistical tests and confidence intervals aregiven for stochastic data28. Uncertainty around cost-effectiveness expressed (e.g.confidence interval around ICER, cost-effectivenessacceptability curves)✓✗

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48TABLE 81 Checklist for EVAR trial participants 46 – Endovascular aneurysm repair and outcome in patients unfit for open repair ofabdominal aortic aneurysm (EVAR trial 2): randomised controlled trial (continued)Study question Grade Comments29. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)Stochastic analysis of decision models30. Are all appropriate input parameters included withuncertainty?31. Is second-order uncertainty (uncertainty in means)included rather than first order (uncertainty betweenpatients)?32. Are the probability distributions adequately detailed andappropriate?33. Sensitivity analysis used to assess uncertainty in nonstochasticvariables (e.g. unit costs, discount rates) andanalytic decisions (e.g. methods to handle missing data)✗N/AN/AN/AN/ADeterministic analysis34. The approach to sensitivity analysis is given (e.g.N/Aunivariate, threshold analysis, etc.)35. The choice of variables for sensitivity analysis is justified N/A36. The ranges over which the variables are varied are stated N/APresentation of results37. Incremental analysis is reported using appropriate N/Adecision rules38. Major outcomes are presented in a disaggregated as well ?as an aggregated form39. Applicable to the NHS setting ✓185© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Appendix 3Survey of health-care resource useafter EVAR and open repairConcerns have been raised by Medtronic 127that the resource use collected from the EVARtrial 1 42 may no longer accurately reflect currentpractice. To inform this issue a postal survey wasconducted on behalf of the evaluation team inJanuary 2008 of members of the Vascular Societyand the British Society of Interventional Radiologyin hospitals in which both EVAR and open repairare undertaken. In total, 55 replies were receivedfrom 50 centres by 25 March 2008 (it should benoted that there has been some duplication fromcentres but because of differences in the responseswe have treated each response as an individualcase). The results of this survey are presented inTable 82.According to the results of the survey, mean daysspent in both intensive care units and generalwards are lower in 2008 after both open repairand EVAR than were found by the EVAR trial 1for patients enrolled between 1999 and 2003.The survey results also indicate that length of stayin general wards may have fallen slightly moreafter EVAR than after open repair, but there isno evidence that the difference between EVARand open repair in the use of high dependencyunit and intensive care unit facilities has changedsubstantially since the EVAR trial 1. The differencein ward length of stay between the treatments inthe EVAR trial 1 was 2.3 days, 43 and the surveyestimates a mean difference in 2008 of 4.3 days.The difference in intensive care unit use betweenthe treatments estimated by EVAR trial 1 was 1.7days, 43 and the survey estimates a mean differenceof 1.1 days.The EVAR trial 1 found that patients attended onaverage two follow-up visits in the first year afterEVAR and one per year thereafter. 43 The results ofthis survey indicate that this is still current practicebut that the frequency of surveillance tends todiminish over time.187© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Appendix 3TABLE 82 Results of the survey of resource use after EVAR and open repairEVAR (55 replies)Open repair (55 replies)Mean (proportion) Median (proportion) Mean (proportion) Median (proportion)Prior to EVAR/open 0.345 0 0.909 1booked? arepair does a criticalcare bed have to beIf one is not availablewould the procedurebe cancelled? a 0.222 0 0.855 1Standard planned postoperative arrangements for EVAR/open repairMean Median Mean MedianDays in ICU 0.019 0 1.167 1Days in HDU 0.519 1 1.600 1Days in general ward 3.037 3 7.309 7Current routine follow-up policy for a patient who has undergone EVAR/open repairMean Median Mean MedianNumber of follow-up outpatient appointments per yearYear 1 2.000 2 1.333 1Year 2 0.759 1 0.164 0Year 3 0.648 1 0.109 0Year 4 0.623 1 0.073 0After year 4 0.635 1 0.073 0Number of CT follow-up appointments per yearYear 1 1.755 2 0.018 0Year 2 0.827 1 0.036 0Year 3 0.712 1 0.018 0Year 4 0.653 1 0.055 0After year 4 0.614 1 0.019 0Number of ultrasound follow-up appointments per yearYear 1 1.265 1 0.057 0Year 2 0.776 1 0.037 0Year 3 0.673 1 0.037 0Year 4 0.681 1 0.037 0After year 4 0.644 1 0.038 0CT, computed tomography; HDU, high dependency unit; ICU, intensive care unit.a 1 indicates yes, 0 indicates no.188

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Appendix 6Characteristics of the average UK populationThe decision model requires inputs such asoperative mortality and non-aneurysmrelatedmortality that are representative of theUK population. The characteristics of the UKpopulation who require aneurysm repair (eitherwith EVAR or open repair) may not be the sameas those of patients recruited to clinical trials orreported in registers. For example, clinical trialsmay select patients who are most anatomicallysuitable for EVAR. If the case mix of the targetpopulation differs from that of the trial or samplepopulation then the estimates from the trial thatare used as inputs to the model must be adjustedfor the appropriate case mix in a consistentmanner.We identify and compare three data sets in whichpatients might have similar characteristics tothe UK population for aneurysm repair: EVARtrial 1, 42,43 RETA 56 and EUROSTAR. 54 Table 83compares the mean age and aneurysm size andoperative mortality of these patients. The studycharacteristics and design of EVAR trial 1 and theRETA and EUROSTAR registries are describedin detail in the assessment of clinical effectivenessassessment report (Chapter 3; see section onassessment of effectiveness from RCTs for EVARtrial 1 and section on assessment of effectivenessfrom registries for RETA and EUROSTAR). Inbrief, EVAR trial 1 included only UK patientsjudged suitable for open repair. The low operativemortality rate (1.7%) may be partly due tofavourable anatomic selection criteria. RETA isa register of UK patients. The average operativemortality rate was 5.8%, but was 1.7% in patientsconsidered fit for open surgery using commerciallyavailable aorto-bi-iliac devices. 56 EUROSTARincluded patients from centres in several Europeancountries using the current generation of devices.The reported operative mortality rate of 2.3%in EUROSTAR includes patients both suitableand unsuitable for open repair, and patients withsmaller aneurysms than are normally operatedon in the UK. On the basis of these sources andclinical opinion it was thought that an operativemortality rate of EVAR of approximately 2% wouldbe fairly representative of average UK practice.In the model in the assessment report, operativemortality is an endogenous variable, that is, it iscalculated as a function of age, aneurysm size andcomorbidities (fitness). This is necessary becauseage and comorbidities have an independent effecton both operative mortality and late mortality.There is a correlation between operative mortalityand late non-aneurysm mortality, operatingthrough age, aneurysm size and comorbidity,that has been incorporated in the structure ofthe model. To populate the model we must selectthe average age, aneurysm size and level ofcomorbidity (relative fitness) of the UK populationthat is consistent with the average mean operativemortality rate after EVAR in the UK population.The risk equation shown in Tables 58 and 59 ofthe assessment report indicates that patients aged75 years with moderate fitness and an aneurysmsize of 6.5 cm are predicted to have an operativemortality rate of 2.1%, similar to our estimate ofthe expected operative mortality rate after EVAR inthe UK population of 2%. From this, we considerthat these characteristics are representative onaverage of the UK population for aneurysm repair.TABLE 83 Comparison of mean age, aneurysm size and operative mortality of patients in EVAR trial 1 and the RETA and EUROSTARregistriesEVAR trial 1 42,43 RETA 56 EUROSTAR 54Age 74 (SD 6.0) years 73 years (range 44–93 years) 73 (SD 7.8) yearsAneurysm size 6.5 (SD 0.9) cm Median 6 cm 5.84 (SD 1.16) cmOperative mortality afterEVAR1.7% 5.8% 2.3%189© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Health Technology Assessment reportspublished to dateVolume 1, 1997No. 1Home parenteral nutrition: a systematicreview.By Richards DM, Deeks JJ, SheldonTA, Shaffer JL.No. 2Diagnosis, management and screeningof early localised prostate cancer.A review by Selley S, Donovan J,Faulkner A, Coast J, Gillatt D.No. 3The diagnosis, management, treatmentand costs of prostate cancer in Englandand Wales.A review by Chamberlain J, Melia J,Moss S, Brown J.No. 4Screening for fragile X syndrome.A review by Murray J, Cuckle H,Taylor G, Hewison J.No. 5A review of near patient testing inprimary care.By Hobbs FDR, Delaney BC,Fitzmaurice DA, Wilson S, Hyde CJ,Thorpe GH, et al.No. 6Systematic review of outpatient servicesfor chronic pain control.By McQuay HJ, Moore RA, EcclestonC, Morley S, de C Williams AC.No. 7Neonatal screening for inborn errors ofmetabolism: cost, yield and outcome.A review by Pollitt RJ, Green A,McCabe CJ, Booth A, Cooper NJ,Leonard JV, et al.No. 8Preschool vision screening.A review by Snowdon SK,Stewart-Brown SL.No. 9Implications of socio-cultural contextsfor the ethics of clinical trials.A review by Ashcroft RE, ChadwickDW, Clark SRL, Edwards RHT, Frith L,Hutton JL.No. 10A critical review of the role of neonatalhearing screening in the detection ofcongenital hearing impairment.By Davis A, Bamford J, Wilson I,Ramkalawan T, Forshaw M, Wright S.No. 11Newborn screening for inborn errors ofmetabolism: a systematic review.By Seymour CA, Thomason MJ,Chalmers RA, Addison GM, Bain MD,Cockburn F, et al.No. 12Routine preoperative testing: asystematic review of the evidence.By Munro J, Booth A, Nicholl J.No. 13Systematic review of the effectiveness oflaxatives in the elderly.By Petticrew M, Watt I, Sheldon T.No. 14When and how to assess fast-changingtechnologies: a comparative study ofmedical applications of four generictechnologies.A review by Mowatt G, Bower DJ,Brebner JA, Cairns JA, Grant AM,McKee L.Volume 2, 1998No. 1Antenatal screening for Down’ssyndrome.A review by Wald NJ, Kennard A,Hackshaw A, McGuire A.No. 2Screening for ovarian cancer: asystematic review.By Bell R, Petticrew M, Luengo S,Sheldon TA.No. 3Consensus development methods,and their use in clinical guidelinedevelopment.A review by Murphy MK, Black NA,Lamping DL, McKee CM, SandersonCFB, Askham J, et al.No. 4A cost–utility analysis of interferon betafor multiple sclerosis.By Parkin D, McNamee P, Jacoby A,Miller P, Thomas S, Bates D.No. 5Effectiveness and efficiency of methodsof dialysis therapy for end-stage renaldisease: systematic reviews.By MacLeod A, Grant A, DonaldsonC, Khan I, Campbell M, Daly C, et al.No. 6Effectiveness of hip prostheses inprimary total hip replacement: a criticalreview of evidence and an economicmodel.By Faulkner A, Kennedy LG, BaxterK, Donovan J, Wilkinson M, Bevan G.No. 7Antimicrobial prophylaxis in colorectalsurgery: a systematic review ofrandomised controlled trials.By Song F, Glenny AM.No. 8Bone marrow and peripheralblood stem cell transplantation formalignancy.A review by Johnson PWM,Simnett SJ, Sweetenham JW, Morgan GJ,Stewart LA.No. 9Screening for speech and languagedelay: a systematic review of theliterature.By Law J, Boyle J, Harris F,Harkness A, Nye C.No. 10Resource allocation for chronicstable angina: a systematicreview of effectiveness, costs andcost-effectiveness of alternativeinterventions.By Sculpher MJ, Petticrew M,Kelland JL, Elliott RA, Holdright DR,Buxton MJ.No. 11Detection, adherence and control ofhypertension for the prevention ofstroke: a systematic review.By Ebrahim S.No. 12Postoperative analgesia and vomiting,with special reference to day-casesurgery: a systematic review.By McQuay HJ, Moore RA.No. 13Choosing between randomised andnonrandomised studies: a systematicreview.By Britton A, McKee M, Black N,McPherson K, Sanderson C, Bain C.No. 14Evaluating patient-based outcomemeasures for use in clinical trials.A review by Fitzpatrick R, Davey C,Buxton MJ, Jones DR.191© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to date192No. 15Ethical issues in the design and conductof randomised controlled trials.A review by Edwards SJL, Lilford RJ,Braunholtz DA, Jackson JC, Hewison J,Thornton J.No. 16Qualitative research methods in healthtechnology assessment: a review of theliterature.By Murphy E, Dingwall R,Greatbatch D, Parker S, Watson P.No. 17The costs and benefits of paramedicskills in pre-hospital trauma care.By Nicholl J, Hughes S, Dixon S,Turner J, Yates D.No. 18Systematic review of endoscopicultrasound in gastro-oesophagealcancer.By Harris KM, Kelly S, Berry E,Hutton J, Roderick P, Cullingworth J,et al.No. 19Systematic reviews of trials and otherstudies.By Sutton AJ, Abrams KR, Jones DR,Sheldon TA, Song F.No. 20Primary total hip replacement surgery:a systematic review of outcomesand modelling of cost-effectivenessassociated with different prostheses.A review by Fitzpatrick R, ShortallE, Sculpher M, Murray D, Morris R,Lodge M, et al.Volume 3, 1999No. 1Informed decision making: anannotated bibliography and systematicreview.By Bekker H, Thornton JG,Airey CM, Connelly JB, Hewison J,Robinson MB, et al.No. 2Handling uncertainty when performingeconomic evaluation of healthcareinterventions.A review by Briggs AH, Gray AM.No. 3The role of expectancies in the placeboeffect and their use in the delivery ofhealth care: a systematic review.By Crow R, Gage H, Hampson S,Hart J, Kimber A, Thomas H.No. 4A randomised controlled trial ofdifferent approaches to universalantenatal HIV testing: uptake andacceptability. Annex: Antenatal HIVtesting – assessment of a routinevoluntary approach.By Simpson WM, Johnstone FD,Boyd FM, Goldberg DJ, Hart GJ,Gormley SM, et al.No. 5Methods for evaluating area-wide andorganisation-based interventions inhealth and health care: a systematicreview.By Ukoumunne OC, Gulliford MC,Chinn S, Sterne JAC, Burney PGJ.No. 6Assessing the costs of healthcaretechnologies in clinical trials.A review by Johnston K, Buxton MJ,Jones DR, Fitzpatrick R.No. 7Cooperatives and their primary careemergency centres: organisation andimpact.By Hallam L, Henthorne K.No. 8Screening for cystic fibrosis.A review by Murray J, Cuckle H,Taylor G, Littlewood J, Hewison J.No. 9A review of the use of health statusmeasures in economic evaluation.By Brazier J, Deverill M, Green C,Harper R, Booth A.No. 10Methods for the analysis of qualityof-lifeand survival data in healthtechnology assessment.A review by Billingham LJ,Abrams KR, Jones DR.No. 11Antenatal and neonatalhaemoglobinopathy screening in theUK: review and economic analysis.By Zeuner D, Ades AE, Karnon J,Brown J, Dezateux C, Anionwu EN.No. 12Assessing the quality of reports ofrandomised trials: implications for theconduct of meta-analyses.A review by Moher D, Cook DJ,Jadad AR, Tugwell P, Moher M,Jones A, et al.No. 13‘Early warning systems’ for identifyingnew healthcare technologies.By Robert G, Stevens A, Gabbay J.No. 14A systematic review of the role ofhuman papillomavirus testing within acervical screening programme.By Cuzick J, Sasieni P, Davies P,Adams J, Normand C, Frater A, et al.No. 15Near patient testing in diabetes clinics:appraising the costs and outcomes.By Grieve R, Beech R, Vincent J,Mazurkiewicz J.No. 16Positron emission tomography:establishing priorities for healthtechnology assessment.A review by Robert G, Milne R.No. 17 (Pt 1)The debridement of chronic wounds: asystematic review.By Bradley M, Cullum N, Sheldon T.No. 17 (Pt 2)Systematic reviews of wound caremanagement: (2) Dressings and topicalagents used in the healing of chronicwounds.By Bradley M, Cullum N, Nelson EA,Petticrew M, Sheldon T, Torgerson D.No. 18A systematic literature review ofspiral and electron beam computedtomography: with particular referenceto clinical applications in hepaticlesions, pulmonary embolus andcoronary artery disease.By Berry E, Kelly S, Hutton J,Harris KM, Roderick P, Boyce JC, et al.No. 19What role for statins? A review andeconomic model.By Ebrahim S, Davey SmithG, McCabe C, Payne N, Pickin M,Sheldon TA, et al.No. 20Factors that limit the quality, numberand progress of randomised controlledtrials.A review by Prescott RJ, Counsell CE,Gillespie WJ, Grant AM, Russell IT,Kiauka S, et al.No. 21Antimicrobial prophylaxis in total hipreplacement: a systematic review.By Glenny AM, Song F.No. 22Health promoting schools and healthpromotion in schools: two systematicreviews.By Lister-Sharp D, Chapman S,Stewart-Brown S, Sowden A.No. 23Economic evaluation of a primarycare-based education programme forpatients with osteoarthritis of the knee.A review by Lord J, Victor C,Littlejohns P, Ross FM, Axford JS.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Volume 4, 2000No. 1The estimation of marginal timepreference in a UK-wide sample(TEMPUS) project.A review by Cairns JA,van der Pol MM.No. 2Geriatric rehabilitation followingfractures in older people: a systematicreview.By Cameron I, Crotty M, Currie C,Finnegan T, Gillespie L, Gillespie W,et al.No. 3Screening for sickle cell disease andthalassaemia: a systematic review withsupplementary research.By Davies SC, Cronin E, Gill M,Greengross P, Hickman M, Normand C.No. 4Community provision of hearing aidsand related audiology services.A review by Reeves DJ, Alborz A,Hickson FS, Bamford JM.No. 5False-negative results in screeningprogrammes: systematic review ofimpact and implications.By Petticrew MP, Sowden AJ,Lister-Sharp D, Wright K.No. 6Costs and benefits of communitypostnatal support workers: arandomised controlled trial.By Morrell CJ, Spiby H, Stewart P,Walters S, Morgan A.No. 7Implantable contraceptives (subdermalimplants and hormonally impregnatedintrauterine systems) versus otherforms of reversible contraceptives: twosystematic reviews to assess relativeeffectiveness, acceptability, tolerabilityand cost-effectiveness.By French RS, Cowan FM,Mansour DJA, Morris S, Procter T,Hughes D, et al.No. 8An introduction to statistical methodsfor health technology assessment.A review by White SJ, Ashby D,Brown PJ.No. 9Disease-modifying drugs for multiplesclerosis: a rapid and systematic review.By Clegg A, Bryant J, Milne R.No. 10Publication and related biases.A review by Song F, Eastwood AJ,Gilbody S, Duley L, Sutton AJ.No. 11Cost and outcome implications of theorganisation of vascular services.By Michaels J, Brazier J,Palfreyman S, Shackley P, Slack R.No. 12Monitoring blood glucose control indiabetes mellitus: a systematic review.By Coster S, Gulliford MC, Seed PT,Powrie JK, Swaminathan R.No. 13The effectiveness of domiciliaryhealth visiting: a systematic review ofinternational studies and a selectivereview of the British literature.By Elkan R, Kendrick D, Hewitt M,Robinson JJA, Tolley K, Blair M, et al.No. 14The determinants of screening uptakeand interventions for increasinguptake: a systematic review.By Jepson R, Clegg A, Forbes C,Lewis R, Sowden A, Kleijnen J.No. 15The effectiveness and cost-effectivenessof prophylactic removal of wisdomteeth.A rapid review by Song F, O’Meara S,Wilson P, Golder S, Kleijnen J.No. 16Ultrasound screening in pregnancy:a systematic review of the clinicaleffectiveness, cost-effectiveness andwomen’s views.By Bricker L, Garcia J, Henderson J,Mugford M, Neilson J, Roberts T, et al.No. 17A rapid and systematic review of theeffectiveness and cost-effectiveness ofthe taxanes used in the treatment ofadvanced breast and ovarian cancer.By Lister-Sharp D, McDonagh MS,Khan KS, Kleijnen J.No. 18Liquid-based cytology in cervicalscreening: a rapid and systematicreview.By Payne N, Chilcott J, McGoogan E.No. 19Randomised controlled trial of nondirectivecounselling, cognitive–behaviour therapy and usual generalpractitioner care in the management ofdepression as well as mixed anxiety anddepression in primary care.By King M, Sibbald B, Ward E,Bower P, Lloyd M, Gabbay M, et al.No. 20Routine referral for radiography ofpatients presenting with low back pain:is patients’ outcome influenced by GPs’referral for plain radiography?By Kerry S, Hilton S, Patel S,Dundas D, Rink E, Lord J.No. 21Systematic reviews of wound caremanagement: (3) antimicrobial agentsfor chronic wounds; (4) diabetic footulceration.By O’Meara S, Cullum N, Majid M,Sheldon T.No. 22Using routine data to complementand enhance the results of randomisedcontrolled trials.By Lewsey JD, Leyland AH, MurrayGD, Boddy FA.No. 23Coronary artery stents in the treatmentof ischaemic heart disease: a rapid andsystematic review.By Meads C, Cummins C, Jolly K,Stevens A, Burls A, Hyde C.No. 24Outcome measures for adult criticalcare: a systematic review.By Hayes JA, Black NA, Jenkinson C,Young JD, Rowan KM, Daly K, et al.No. 25A systematic review to evaluate theeffectiveness of interventions topromote the initiation of breastfeeding.By Fairbank L, O’Meara S,Renfrew MJ, Woolridge M, Sowden AJ,Lister-Sharp D.No. 26Implantable cardioverter defibrillators:arrhythmias. A rapid and systematicreview.By Parkes J, Bryant J, Milne R.No. 27Treatments for fatigue in multiplesclerosis: a rapid and systematic review.By Brañas P, Jordan R, Fry-Smith A,Burls A, Hyde C.No. 28Early asthma prophylaxis, naturalhistory, skeletal development andeconomy (EASE): a pilot randomisedcontrolled trial.By Baxter-Jones ADG, Helms PJ,Russell G, Grant A, Ross S, Cairns JA,et al.No. 29Screening for hypercholesterolaemiaversus case finding for familialhypercholesterolaemia: a systematicreview and cost-effectiveness analysis.By Marks D, WonderlingD, Thorogood M, Lambert H,Humphries SE, Neil HAW.No. 30A rapid and systematic review ofthe clinical effectiveness and costeffectivenessof glycoprotein IIb/IIIaantagonists in the medical managementof unstable angina.By McDonagh MS, Bachmann LM,Golder S, Kleijnen J, ter Riet G.193© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to date194No. 31A randomised controlled trialof prehospital intravenous fluidreplacement therapy in serious trauma.By Turner J, Nicholl J, Webber L,Cox H, Dixon S, Yates D.No. 32Intrathecal pumps for giving opioids inchronic pain: a systematic review.By Williams JE, Louw G,Towlerton G.No. 33Combination therapy (interferonalfa and ribavirin) in the treatmentof chronic hepatitis C: a rapid andsystematic review.By Shepherd J, Waugh N,Hewitson P.No. 34A systematic review of comparisons ofeffect sizes derived from randomisedand non-randomised studies.By MacLehose RR, Reeves BC,Harvey IM, Sheldon TA, Russell IT,Black AMS.No. 35Intravascular ultrasound-guidedinterventions in coronary arterydisease: a systematic literature review,with decision-analytic modelling, ofoutcomes and cost-effectiveness.By Berry E, Kelly S, Hutton J,Lindsay HSJ, Blaxill JM, Evans JA, et al.No. 36A randomised controlled trial toevaluate the effectiveness and costeffectivenessof counselling patientswith chronic depression.By Simpson S, Corney R,Fitzgerald P, Beecham J.No. 37Systematic review of treatments foratopic eczema.By Hoare C, Li Wan Po A,Williams H.No. 38Bayesian methods in health technologyassessment: a review.By Spiegelhalter DJ, Myles JP,Jones DR, Abrams KR.No. 39The management of dyspepsia: asystematic review.By Delaney B, Moayyedi P, Deeks J,Innes M, Soo S, Barton P, et al.No. 40A systematic review of treatments forsevere psoriasis.By Griffiths CEM, Clark CM,Chalmers RJG, Li Wan Po A,Williams HC.Volume 5, 2001No. 1Clinical and cost-effectivenessof donepezil, rivastigmine andgalantamine for Alzheimer’s disease: arapid and systematic review.By Clegg A, Bryant J, Nicholson T,McIntyre L, De Broe S, Gerard K, et al.No. 2The clinical effectiveness and costeffectivenessof riluzole for motorneurone disease: a rapid and systematicreview.By Stewart A, Sandercock J, Bryan S,Hyde C, Barton PM, Fry-Smith A, et al.No. 3Equity and the economic evaluation ofhealthcare.By Sassi F, Archard L, Le Grand J.No. 4Quality-of-life measures in chronicdiseases of childhood.By Eiser C, Morse R.No. 5Eliciting public preferences forhealthcare: a systematic review oftechniques.By Ryan M, Scott DA, Reeves C, BateA, van Teijlingen ER, Russell EM, et al.No. 6General health status measures forpeople with cognitive impairment:learning disability and acquired braininjury.By Riemsma RP, Forbes CA,Glanville JM, Eastwood AJ, Kleijnen J.No. 7An assessment of screening strategiesfor fragile X syndrome in the UK.By Pembrey ME, Barnicoat AJ,Carmichael B, Bobrow M, Turner G.No. 8Issues in methodological research:perspectives from researchers andcommissioners.By Lilford RJ, Richardson A, StevensA, Fitzpatrick R, Edwards S, Rock F, et al.No. 9Systematic reviews of woundcare management: (5) beds;(6) compression; (7) laser therapy,therapeutic ultrasound, electrotherapyand electromagnetic therapy.By Cullum N, Nelson EA,Flemming K, Sheldon T.No. 10Effects of educational and psychosocialinterventions for adolescents withdiabetes mellitus: a systematic review.By Hampson SE, Skinner TC, Hart J,Storey L, Gage H, Foxcroft D, et al.No. 11Effectiveness of autologous chondrocytetransplantation for hyaline cartilagedefects in knees: a rapid and systematicreview.By Jobanputra P, Parry D, Fry-SmithA, Burls A.No. 12Statistical assessment of the learningcurves of health technologies.By Ramsay CR, Grant AM, WallaceSA, Garthwaite PH, Monk AF, Russell IT.No. 13The effectiveness and cost-effectivenessof temozolomide for the treatment ofrecurrent malignant glioma: a rapidand systematic review.By Dinnes J, Cave C, Huang S,Major K, Milne R.No. 14A rapid and systematic review ofthe clinical effectiveness and costeffectivenessof debriding agents intreating surgical wounds healing bysecondary intention.By Lewis R, Whiting P, ter Riet G,O’Meara S, Glanville J.No. 15Home treatment for mental healthproblems: a systematic review.By Burns T, Knapp M, Catty J,Healey A, Henderson J, Watt H, et al.No. 16How to develop cost-consciousguidelines.By Eccles M, Mason J.No. 17The role of specialist nurses in multiplesclerosis: a rapid and systematic review.By De Broe S, Christopher F,Waugh N.No. 18A rapid and systematic reviewof the clinical effectiveness andcost-effectiveness of orlistat in themanagement of obesity.By O’Meara S, Riemsma R,Shirran L, Mather L, ter Riet G.No. 19The clinical effectiveness and costeffectivenessof pioglitazone fortype 2 diabetes mellitus: a rapid andsystematic review.By Chilcott J, Wight J, Lloyd JonesM, Tappenden P.No. 20Extended scope of nursing practice:a multicentre randomised controlledtrial of appropriately trained nursesand preregistration house officers inpreoperative assessment in electivegeneral surgery.By Kinley H, Czoski-Murray C,George S, McCabe C, Primrose J,Reilly C, et al.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 21Systematic reviews of the effectivenessof day care for people with severemental disorders: (1) Acute day hospitalversus admission; (2) Vocationalrehabilitation; (3) Day hospital versusoutpatient care.By Marshall M, Crowther R,Almaraz- Serrano A, Creed F, Sledge W,Kluiter H, et al.No. 22The measurement and monitoring ofsurgical adverse events.By Bruce J, Russell EM, Mollison J,Krukowski ZH.No. 31Design and use of questionnaires: areview of best practice applicable tosurveys of health service staff andpatients.By McColl E, Jacoby A, Thomas L,Soutter J, Bamford C, Steen N, et al.No. 32A rapid and systematic review ofthe clinical effectiveness and costeffectivenessof paclitaxel, docetaxel,gemcitabine and vinorelbine in nonsmall-celllung cancer.By Clegg A, Scott DA, Sidhu M,Hewitson P, Waugh N.No. 5The clinical effectiveness and costeffectivenessof inhaler devices usedin the routine management of chronicasthma in older children: a systematicreview and economic evaluation.By Peters J, Stevenson M, Beverley C,Lim J, Smith S.No. 6The clinical effectiveness and costeffectivenessof sibutramine in themanagement of obesity: a technologyassessment.By O’Meara S, Riemsma R, ShirranL, Mather L, ter Riet G.No. 23Action research: a systematic review andguidance for assessment.By Waterman H, Tillen D, Dickson R,de Koning K.No. 24A rapid and systematic review ofthe clinical effectiveness and costeffectivenessof gemcitabine for thetreatment of pancreatic cancer.By Ward S, Morris E, Bansback N,Calvert N, Crellin A, Forman D, et al.No. 25A rapid and systematic review of theevidence for the clinical effectivenessand cost-effectiveness of irinotecan,oxaliplatin and raltitrexed for thetreatment of advanced colorectalcancer.By Lloyd Jones M, Hummel S,Bansback N, Orr B, Seymour M.No. 26Comparison of the effectiveness ofinhaler devices in asthma and chronicobstructive airways disease: a systematicreview of the literature.By Brocklebank D, Ram F, Wright J,Barry P, Cates C, Davies L, et al.No. 27The cost-effectiveness of magneticresonance imaging for investigation ofthe knee joint.By Bryan S, Weatherburn G, BungayH, Hatrick C, Salas C, Parry D, et al.No. 28A rapid and systematic review ofthe clinical effectiveness and costeffectivenessof topotecan for ovariancancer.By Forbes C, Shirran L, Bagnall A-M,Duffy S, ter Riet G.No. 29Superseded by a report published in alater volume.No. 30The role of radiography in primarycare patients with low back pain of atleast 6 weeks duration: a randomised(unblinded) controlled trial.By Kendrick D, Fielding K, BentleyE, Miller P, Kerslake R, Pringle M.No. 33Subgroup analyses in randomisedcontrolled trials: quantifying the risksof false-positives and false-negatives.By Brookes ST, Whitley E, Peters TJ,Mulheran PA, Egger M, Davey Smith G.No. 34Depot antipsychotic medicationin the treatment of patients withschizophrenia: (1) Meta-review; (2)Patient and nurse attitudes.By David AS, Adams C.No. 35A systematic review of controlledtrials of the effectiveness and costeffectivenessof brief psychologicaltreatments for depression.By Churchill R, Hunot V, Corney R,Knapp M, McGuire H, Tylee A, et al.No. 36Cost analysis of child healthsurveillance.By Sanderson D, Wright D, Acton C,Duree D.Volume 6, 2002No. 1A study of the methods used to selectreview criteria for clinical audit.By Hearnshaw H, Harker R,Cheater F, Baker R, Grimshaw G.No. 2Fludarabine as second-line therapy forB cell chronic lymphocytic leukaemia: atechnology assessment.By Hyde C, Wake B, Bryan S, BartonP, Fry-Smith A, Davenport C, et al.No. 3Rituximab as third-line treatment forrefractory or recurrent Stage III or IVfollicular non-Hodgkin’s lymphoma:a systematic review and economicevaluation.By Wake B, Hyde C, Bryan S, BartonP, Song F, Fry-Smith A, et al.No. 4A systematic review of dischargearrangements for older people.By Parker SG, Peet SM, McPhersonA, Cannaby AM, Baker R, Wilson A, et al.No. 7The cost-effectiveness of magneticresonance angiography for carotidartery stenosis and peripheral vasculardisease: a systematic review.By Berry E, Kelly S, Westwood ME,Davies LM, Gough MJ, Bamford JM,et al.No. 8Promoting physical activity in SouthAsian Muslim women through ‘exerciseon prescription’.By Carroll B, Ali N, Azam N.No. 9Zanamivir for the treatment ofinfluenza in adults: a systematic reviewand economic evaluation.By Burls A, Clark W, Stewart T,Preston C, Bryan S, Jefferson T, et al.No. 10A review of the natural history andepidemiology of multiple sclerosis:implications for resource allocation andhealth economic models.By Richards RG, Sampson FC,Beard SM, Tappenden P.No. 11Screening for gestational diabetes:a systematic review and economicevaluation.By Scott DA, Loveman E, McIntyreL, Waugh N.No. 12The clinical effectiveness and costeffectivenessof surgery for people withmorbid obesity: a systematic review andeconomic evaluation.By Clegg AJ, Colquitt J, Sidhu MK,Royle P, Loveman E, Walker A.No. 13The clinical effectiveness oftrastuzumab for breast cancer: asystematic review.By Lewis R, Bagnall A-M, Forbes C,Shirran E, Duffy S, Kleijnen J, et al.No. 14The clinical effectiveness and costeffectivenessof vinorelbine for breastcancer: a systematic review andeconomic evaluation.By Lewis R, Bagnall A-M, King S,Woolacott N, Forbes C, Shirran L, et al.195© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to dateNo. 15A systematic review of the effectivenessand cost-effectiveness of metal-onmetalhip resurfacing arthroplasty fortreatment of hip disease.By Vale L, Wyness L, McCormack K,McKenzie L, Brazzelli M, Stearns SC.No. 16The clinical effectiveness and costeffectivenessof bupropion and nicotinereplacement therapy for smokingcessation: a systematic review andeconomic evaluation.By Woolacott NF, Jones L, Forbes CA,Mather LC, Sowden AJ, Song FJ, et al.No. 17A systematic review of effectivenessand economic evaluation of new drugtreatments for juvenile idiopathicarthritis: etanercept.By Cummins C, Connock M,Fry-Smith A, Burls A.No. 24A systematic review of the effectivenessof interventions based on a stages-ofchangeapproach to promote individualbehaviour change.By Riemsma RP, Pattenden J, BridleC, Sowden AJ, Mather L, Watt IS, et al.No. 25A systematic review update of theclinical effectiveness and costeffectivenessof glycoprotein IIb/IIIaantagonists.By Robinson M, Ginnelly L, SculpherM, Jones L, Riemsma R, Palmer S, et al.No. 26A systematic review of the effectiveness,cost-effectiveness and barriers toimplementation of thrombolytic andneuroprotective therapy for acuteischaemic stroke in the NHS.By Sandercock P, Berge E, Dennis M,Forbes J, Hand P, Kwan J, et al.No. 33The effectiveness and cost-effectivenessof imatinib in chronic myeloidleukaemia: a systematic review.By Garside R, Round A, Dalziel K,Stein K, Royle R.No. 34A comparative study of hypertonicsaline, daily and alternate-day rhDNasein children with cystic fibrosis.By Suri R, Wallis C, Bush A,Thompson S, Normand C, Flather M,et al.No. 35A systematic review of the costs andeffectiveness of different models ofpaediatric home care.By Parker G, Bhakta P, Lovett CA,Paisley S, Olsen R, Turner D, et al.Volume 7, 2003196No. 18Clinical effectiveness and costeffectivenessof growth hormone inchildren: a systematic review andeconomic evaluation.By Bryant J, Cave C, Mihaylova B,Chase D, McIntyre L, Gerard K, et al.No. 19Clinical effectiveness and costeffectivenessof growth hormonein adults in relation to impact onquality of life: a systematic review andeconomic evaluation.By Bryant J, Loveman E, Chase D,Mihaylova B, Cave C, Gerard K, et al.No. 20Clinical medication review by apharmacist of patients on repeatprescriptions in general practice: arandomised controlled trial.By Zermansky AG, Petty DR, RaynorDK, Lowe CJ, Freementle N, Vail A.No. 21The effectiveness of infliximab andetanercept for the treatment ofrheumatoid arthritis: a systematicreview and economic evaluation.By Jobanputra P, Barton P, Bryan S,Burls A.No. 22A systematic review and economicevaluation of computerised cognitivebehaviour therapy for depression andanxiety.By Kaltenthaler E, Shackley P,Stevens K, Beverley C, Parry G,Chilcott J.No. 23A systematic review and economicevaluation of pegylated liposomaldoxorubicin hydrochloride for ovariancancer.By Forbes C, Wilby J, Richardson G,Sculpher M, Mather L, Reimsma R.No. 27A randomised controlled crossover trialof nurse practitioner versus doctorledoutpatient care in a bronchiectasisclinic.By Caine N, Sharples LD,Hollingworth W, French J, Keogan M,Exley A, et al.No. 28Clinical effectiveness and cost –consequences of selective serotoninreuptake inhibitors in the treatment ofsex offenders.By Adi Y, Ashcroft D, Browne K,Beech A, Fry-Smith A, Hyde C.No. 29Treatment of established osteoporosis:a systematic review and cost–utilityanalysis.By Kanis JA, Brazier JE, StevensonM, Calvert NW, Lloyd Jones M.No. 30Which anaesthetic agents are costeffectivein day surgery? Literaturereview, national survey of practice andrandomised controlled trial.By Elliott RA Payne K, Moore JK,Davies LM, Harper NJN, St Leger AS,et al.No. 31Screening for hepatitis C amonginjecting drug users and ingenitourinary medicine clinics:systematic reviews of effectiveness,modelling study and national survey ofcurrent practice.By Stein K, Dalziel K, Walker A,McIntyre L, Jenkins B, Horne J, et al.No. 32The measurement of satisfaction withhealthcare: implications for practicefrom a systematic review of theliterature.By Crow R, Gage H, Hampson S,Hart J, Kimber A, Storey L, et al.No. 1How important are comprehensiveliterature searches and the assessmentof trial quality in systematic reviews?Empirical study.By Egger M, Jüni P, Bartlett C,Holenstein F, Sterne J.No. 2Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of home versus hospital orsatellite unit haemodialysis for peoplewith end-stage renal failure.By Mowatt G, Vale L, Perez J, WynessL, Fraser C, MacLeod A, et al.No. 3Systematic review and economicevaluation of the effectiveness ofinfliximab for the treatment of Crohn’sdisease.By Clark W, Raftery J, Barton P,Song F, Fry-Smith A, Burls A.No. 4A review of the clinical effectivenessand cost-effectiveness of routine anti-Dprophylaxis for pregnant women whoare rhesus negative.By Chilcott J, Lloyd Jones M, WightJ, Forman K, Wray J, Beverley C, et al.No. 5Systematic review and evaluation of theuse of tumour markers in paediatriconcology: Ewing’s sarcoma andneuroblastoma.By Riley RD, Burchill SA,Abrams KR, Heney D, Lambert PC,Jones DR, et al.No. 6The cost-effectiveness of screening forHelicobacter pylori to reduce mortalityand morbidity from gastric cancer andpeptic ulcer disease: a discrete-eventsimulation model.By Roderick P, Davies R, Raftery J,Crabbe D, Pearce R, Bhandari P, et al.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 7The clinical effectiveness and costeffectivenessof routine dental checks:a systematic review and economicevaluation.By Davenport C, Elley K, SalasC, Taylor-Weetman CL, Fry-Smith A,Bryan S, et al.No. 8A multicentre randomised controlledtrial assessing the costs and benefitsof using structured information andanalysis of women’s preferences in themanagement of menorrhagia.By Kennedy ADM, Sculpher MJ,Coulter A, Dwyer N, Rees M, Horsley S,et al.No. 9Clinical effectiveness and cost–utilityof photodynamic therapy for wetage-related macular degeneration:a systematic review and economicevaluation.By Meads C, Salas C, Roberts T,Moore D, Fry-Smith A, Hyde C.No. 10Evaluation of molecular tests forprenatal diagnosis of chromosomeabnormalities.By Grimshaw GM, Szczepura A,Hultén M, MacDonald F, Nevin NC,Sutton F, et al.No. 11First and second trimester antenatalscreening for Down’s syndrome:the results of the Serum, Urine andUltrasound Screening Study (SURUSS).By Wald NJ, Rodeck C, HackshawAK, Walters J, Chitty L, Mackinson AM.No. 12The effectiveness and cost-effectivenessof ultrasound locating devices forcentral venous access: a systematicreview and economic evaluation.By Calvert N, Hind D, McWilliamsRG, Thomas SM, Beverley C,Davidson A.No. 13A systematic review of atypicalantipsychotics in schizophrenia.By Bagnall A-M, Jones L, Lewis R,Ginnelly L, Glanville J, Torgerson D,et al.No. 14Prostate Testing for Cancer andTreatment (ProtecT) feasibility study.By Donovan J, Hamdy F, Neal D,Peters T, Oliver S, Brindle L, et al.No. 15Early thrombolysis for the treatmentof acute myocardial infarction: asystematic review and economicevaluation.By Boland A, Dundar Y, Bagust A,Haycox A, Hill R, Mujica Mota R, et al.No. 16Screening for fragile X syndrome: aliterature review and modelling.By Song FJ, Barton P, SleightholmeV, Yao GL, Fry-Smith A.No. 17Systematic review of endoscopic sinussurgery for nasal polyps.By Dalziel K, Stein K, Round A,Garside R, Royle P.No. 18Towards efficient guidelines: how tomonitor guideline use in primary care.By Hutchinson A, McIntosh A,Cox S, Gilbert C.No. 19Effectiveness and cost-effectivenessof acute hospital-based spinal cordinjuries services: systematic review.By Bagnall A-M, Jones L, RichardsonG, Duffy S, Riemsma R.No. 20Prioritisation of health technologyassessment. The PATHS model:methods and case studies.By Townsend J, Buxton M,Harper G.No. 21Systematic review of the clinicaleffectiveness and cost-effectiveness oftension-free vaginal tape for treatmentof urinary stress incontinence.By Cody J, Wyness L, Wallace S,Glazener C, Kilonzo M, Stearns S, et al.No. 22The clinical and cost-effectiveness ofpatient education models for diabetes:a systematic review and economicevaluation.By Loveman E, Cave C, Green C,Royle P, Dunn N, Waugh N.No. 23The role of modelling in prioritisingand planning clinical trials.By Chilcott J, Brennan A, Booth A,Karnon J, Tappenden P.No. 24Cost–benefit evaluation of routineinfluenza immunisation in people65–74 years of age.By Allsup S, Gosney M, Haycox A,Regan M.No. 25The clinical and cost-effectiveness ofpulsatile machine perfusion versus coldstorage of kidneys for transplantationretrieved from heart-beating and nonheart-beatingdonors.By Wight J, Chilcott J, Holmes M,Brewer N.No. 26Can randomised trials rely on existingelectronic data? A feasibility study toexplore the value of routine data inhealth technology assessment.By Williams JG, Cheung WY,Cohen DR, Hutchings HA, Longo MF,Russell IT.No. 27Evaluating non-randomisedintervention studies.By Deeks JJ, Dinnes J, D’Amico R,Sowden AJ, Sakarovitch C, Song F, et al.No. 28A randomised controlled trial to assessthe impact of a package comprising apatient-orientated, evidence-based selfhelpguidebook and patient-centredconsultations on disease managementand satisfaction in inflammatory boweldisease.By Kennedy A, Nelson E, Reeves D,Richardson G, Roberts C, Robinson A,et al.No. 29The effectiveness of diagnostic tests forthe assessment of shoulder pain dueto soft tissue disorders: a systematicreview.By Dinnes J, Loveman E, McIntyre L,Waugh N.No. 30The value of digital imaging in diabeticretinopathy.By Sharp PF, Olson J, Strachan F,Hipwell J, Ludbrook A, O’Donnell M,et al.No. 31Lowering blood pressure to preventmyocardial infarction and stroke: a newpreventive strategy.By Law M, Wald N, Morris J.No. 32Clinical and cost-effectiveness ofcapecitabine and tegafur with uracil forthe treatment of metastatic colorectalcancer: systematic review and economicevaluation.By Ward S, Kaltenthaler E, Cowan J,Brewer N.No. 33Clinical and cost-effectiveness of newand emerging technologies for earlylocalised prostate cancer: a systematicreview.By Hummel S, Paisley S, Morgan A,Currie E, Brewer N.No. 34Literature searching for clinical andcost-effectiveness studies used in healthtechnology assessment reports carriedout for the National Institute forClinical Excellence appraisal system.By Royle P, Waugh N.197© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to dateNo. 35Systematic review and economicdecision modelling for the preventionand treatment of influenza A and B.By Turner D, Wailoo A, Nicholson K,Cooper N, Sutton A, Abrams K.No. 36A randomised controlled trialto evaluate the clinical and costeffectivenessof Hickman line insertionsin adult cancer patients by nurses.By Boland A, Haycox A, Bagust A,Fitzsimmons L.No. 37Redesigning postnatal care: arandomised controlled trial of protocolbasedmidwifery-led care focusedon individual women’s physical andpsychological health needs.By MacArthur C, Winter HR,Bick DE, Lilford RJ, Lancashire RJ,Knowles H, et al.No. 38Estimating implied rates of discount inhealthcare decision-making.By West RR, McNabb R, ThompsonAGH, Sheldon TA, Grimley Evans J.No. 39Systematic review of isolation policiesin the hospital management ofmethicillin-resistant Staphylococcusaureus: a review of the literaturewith epidemiological and economicmodelling.By Cooper BS, Stone SP, Kibbler CC,Cookson BD, Roberts JA, Medley GF,et al.No. 40Treatments for spasticity and pain inmultiple sclerosis: a systematic review.By Beard S, Hunn A, Wight J.No. 41The inclusion of reports of randomisedtrials published in languages other thanEnglish in systematic reviews.By Moher D, Pham B, Lawson ML,Klassen TP.No. 2Systematic review and modelling of theinvestigation of acute and chronic chestpain presenting in primary care.By Mant J, McManus RJ, Oakes RAL,Delaney BC, Barton PM, Deeks JJ, et al.No. 3The effectiveness and cost-effectivenessof microwave and thermal balloonendometrial ablation for heavymenstrual bleeding: a systematic reviewand economic modelling.By Garside R, Stein K, Wyatt K,Round A, Price A.No. 4A systematic review of the role ofbisphosphonates in metastatic disease.By Ross JR, Saunders Y,Edmonds PM, Patel S, Wonderling D,Normand C, et al.No. 5Systematic review of the clinicaleffectiveness and cost-effectivenessof capecitabine (Xeloda ® ) for locallyadvanced and/or metastatic breastcancer.By Jones L, Hawkins N, Westwood M,Wright K, Richardson G, Riemsma R.No. 6Effectiveness and efficiency of guidelinedissemination and implementationstrategies.By Grimshaw JM, Thomas RE,MacLennan G, Fraser C, Ramsay CR,Vale L, et al.No. 7Clinical effectiveness and costs of theSugarbaker procedure for the treatmentof pseudomyxoma peritonei.By Bryant J, Clegg AJ, Sidhu MK,Brodin H, Royle P, Davidson P.No. 8Psychological treatment for insomniain the regulation of long-term hypnoticdrug use.By Morgan K, Dixon S, Mathers N,Thompson J, Tomeny M.No. 11The use of modelling to evaluatenew drugs for patients with a chroniccondition: the case of antibodiesagainst tumour necrosis factor inrheumatoid arthritis.By Barton P, Jobanputra P, Wilson J,Bryan S, Burls A.No. 12Clinical effectiveness and costeffectivenessof neonatal screeningfor inborn errors of metabolism usingtandem mass spectrometry: a systematicreview.By Pandor A, Eastham J, Beverley C,Chilcott J, Paisley S.No. 13Clinical effectiveness and costeffectivenessof pioglitazone androsiglitazone in the treatment of type2 diabetes: a systematic review andeconomic evaluation.By Czoski-Murray C, Warren E,Chilcott J, Beverley C, Psyllaki MA,Cowan J.No. 14Routine examination of the newborn:the EMREN study. Evaluation of anextension of the midwife role includinga randomised controlled trial ofappropriately trained midwives andpaediatric senior house officers.By Townsend J, Wolke D, Hayes J,Davé S, Rogers C, Bloomfield L, et al.No. 15Involving consumers in research anddevelopment agenda setting for theNHS: developing an evidence-basedapproach.By Oliver S, Clarke-Jones L, Rees R,Milne R, Buchanan P, Gabbay J, et al.No. 16A multi-centre randomised controlledtrial of minimally invasive directcoronary bypass grafting versuspercutaneous transluminal coronaryangioplasty with stenting for proximalstenosis of the left anterior descendingcoronary artery.By Reeves BC, Angelini GD, BryanAJ, Taylor FC, Cripps T, Spyt TJ, et al.198No. 42The impact of screening on futurehealth-promoting behaviours andhealth beliefs: a systematic review.By Bankhead CR, Brett J, Bukach C,Webster P, Stewart-Brown S, Munafo M,et al.Volume 8, 2004No. 1What is the best imaging strategy foracute stroke?By Wardlaw JM, Keir SL, Seymour J,Lewis S, Sandercock PAG, Dennis MS,et al.No. 9Improving the evaluation oftherapeutic interventions in multiplesclerosis: development of a patientbasedmeasure of outcome.By Hobart JC, Riazi A, Lamping DL,Fitzpatrick R, Thompson AJ.No. 10A systematic review and economicevaluation of magnetic resonancecholangiopancreatography comparedwith diagnostic endoscopic retrogradecholangiopancreatography.By Kaltenthaler E, Bravo Vergel Y,Chilcott J, Thomas S, Blakeborough T,Walters SJ, et al.No. 17Does early magnetic resonance imaginginfluence management or improveoutcome in patients referred tosecondary care with low back pain? Apragmatic randomised controlled trial.By Gilbert FJ, Grant AM, GillanMGC, Vale L, Scott NW, Campbell MK,et al.No. 18The clinical and cost-effectivenessof anakinra for the treatment ofrheumatoid arthritis in adults: asystematic review and economicanalysis.By Clark W, Jobanputra P, Barton P,Burls A.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 19A rapid and systematic review andeconomic evaluation of the clinicaland cost-effectiveness of newer drugsfor treatment of mania associated withbipolar affective disorder.By Bridle C, Palmer S, Bagnall A-M,Darba J, Duffy S, Sculpher M, et al.No. 20Liquid-based cytology in cervicalscreening: an updated rapid andsystematic review and economicanalysis.By Karnon J, Peters J, Platt J,Chilcott J, McGoogan E, Brewer N.No. 21Systematic review of the long-termeffects and economic consequences oftreatments for obesity and implicationsfor health improvement.By Avenell A, Broom J, Brown TJ,Poobalan A, Aucott L, Stearns SC, et al.No. 22Autoantibody testing in childrenwith newly diagnosed type 1 diabetesmellitus.By Dretzke J, Cummins C,Sandercock J, Fry-Smith A, Barrett T,Burls A.No. 23Clinical effectiveness and costeffectivenessof prehospital intravenousfluids in trauma patients.By Dretzke J, Sandercock J, BaylissS, Burls A.No. 24Newer hypnotic drugs for the shorttermmanagement of insomnia: asystematic review and economicevaluation.By Dündar Y, Boland A, Strobl J,Dodd S, Haycox A, Bagust A, et al.No. 25Development and validation ofmethods for assessing the quality ofdiagnostic accuracy studies.By Whiting P, Rutjes AWS, Dinnes J,Reitsma JB, Bossuyt PMM, Kleijnen J.No. 26EVALUATE hysterectomy trial:a multicentre randomised trialcomparing abdominal, vaginal andlaparoscopic methods of hysterectomy.By Garry R, Fountain J, Brown J,Manca A, Mason S, Sculpher M, et al.No. 27Methods for expected value ofinformation analysis in complex healtheconomic models: developments onthe health economics of interferon-βand glatiramer acetate for multiplesclerosis.By Tappenden P, Chilcott JB,Eggington S, Oakley J, McCabe C.No. 28Effectiveness and cost-effectivenessof imatinib for first-line treatmentof chronic myeloid leukaemia inchronic phase: a systematic review andeconomic analysis.By Dalziel K, Round A, Stein K,Garside R, Price A.No. 29VenUS I: a randomised controlled trialof two types of bandage for treatingvenous leg ulcers.By Iglesias C, Nelson EA, CullumNA, Torgerson DJ, on behalf of theVenUS Team.No. 30Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of myocardial perfusionscintigraphy for the diagnosis andmanagement of angina and myocardialinfarction.By Mowatt G, Vale L, Brazzelli M,Hernandez R, Murray A, Scott N, et al.No. 31A pilot study on the use of decisiontheory and value of informationanalysis as part of the NHS HealthTechnology Assessment programme.By Claxton K, Ginnelly L, SculpherM, Philips Z, Palmer S.No. 32The Social Support and Family HealthStudy: a randomised controlled trialand economic evaluation of twoalternative forms of postnatal supportfor mothers living in disadvantagedinner-city areas.By Wiggins M, Oakley A, Roberts I,Turner H, Rajan L, Austerberry H, et al.No. 33Psychosocial aspects of geneticscreening of pregnant women andnewborns: a systematic review.By Green JM, Hewison J, Bekker HL,Bryant, Cuckle HS.No. 34Evaluation of abnormal uterinebleeding: comparison of threeoutpatient procedures within cohortsdefined by age and menopausal status.By Critchley HOD, Warner P, Lee AJ,Brechin S, Guise J, Graham B.No. 35Coronary artery stents: a rapidsystematic review and economicevaluation.By Hill R, Bagust A, Bakhai A,Dickson R, Dündar Y, Haycox A, et al.No. 36Review of guidelines for good practicein decision-analytic modelling in healthtechnology assessment.By Philips Z, Ginnelly L, Sculpher M,Claxton K, Golder S, Riemsma R, et al.No. 37Rituximab (MabThera ® ) for aggressivenon-Hodgkin’s lymphoma: systematicreview and economic evaluation.By Knight C, Hind D, Brewer N,Abbott V.No. 38Clinical effectiveness and costeffectivenessof clopidogrel andmodified-release dipyridamole in thesecondary prevention of occlusivevascular events: a systematic review andeconomic evaluation.By Jones L, Griffin S, Palmer S, MainC, Orton V, Sculpher M, et al.No. 39Pegylated interferon α-2a and -2bin combination with ribavirin in thetreatment of chronic hepatitis C:a systematic review and economicevaluation.By Shepherd J, Brodin H, Cave C,Waugh N, Price A, Gabbay J.No. 40Clopidogrel used in combination withaspirin compared with aspirin alonein the treatment of non-ST-segmentelevationacute coronary syndromes:a systematic review and economicevaluation.By Main C, Palmer S, Griffin S, JonesL, Orton V, Sculpher M, et al.No. 41Provision, uptake and cost of cardiacrehabilitation programmes: improvingservices to under-represented groups.By Beswick AD, Rees K, Griebsch I,Taylor FC, Burke M, West RR, et al.No. 42Involving South Asian patients inclinical trials.By Hussain-Gambles M, Leese B,Atkin K, Brown J, Mason S, Tovey P.No. 43Clinical and cost-effectiveness ofcontinuous subcutaneous insulininfusion for diabetes.By Colquitt JL, Green C, Sidhu MK,Hartwell D, Waugh N.No. 44Identification and assessment ofongoing trials in health technologyassessment reviews.By Song FJ, Fry-Smith A, DavenportC, Bayliss S, Adi Y, Wilson JS, et al.No. 45Systematic review and economicevaluation of a long-acting insulinanalogue, insulin glargineBy Warren E, Weatherley-Jones E,Chilcott J, Beverley C.199© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to date200No. 46Supplementation of a home-basedexercise programme with a classbasedprogramme for peoplewith osteoarthritis of the knees: arandomised controlled trial and healtheconomic analysis.By McCarthy CJ, Mills PM, Pullen R,Richardson G, Hawkins N, Roberts CR,et al.No. 47Clinical and cost-effectiveness of oncedailyversus more frequent use of samepotency topical corticosteroids foratopic eczema: a systematic review andeconomic evaluation.By Green C, Colquitt JL, Kirby J,Davidson P, Payne E.No. 48Acupuncture of chronic headachedisorders in primary care: randomisedcontrolled trial and economic analysis.By Vickers AJ, Rees RW, Zollman CE,McCarney R, Smith CM, Ellis N, et al.No. 49Generalisability in economic evaluationstudies in healthcare: a review and casestudies.By Sculpher MJ, Pang FS, Manca A,Drummond MF, Golder S, Urdahl H,et al.No. 50Virtual outreach: a randomisedcontrolled trial and economicevaluation of joint teleconferencedmedical consultations.By Wallace P, Barber J, Clayton W,Currell R, Fleming K, Garner P, et al.Volume 9, 2005No. 1Randomised controlled multipletreatment comparison to provide a costeffectivenessrationale for the selectionof antimicrobial therapy in acne.By Ozolins M, Eady EA, Avery A,Cunliffe WJ, O’Neill C, Simpson NB,et al.No. 2Do the findings of case series studiesvary significantly according tomethodological characteristics?By Dalziel K, Round A, Stein K,Garside R, Castelnuovo E, Payne L.No. 3Improving the referral processfor familial breast cancer geneticcounselling: findings of threerandomised controlled trials of twointerventions.By Wilson BJ, Torrance N,Mollison J, Wordsworth S, Gray JR,Haites NE, et al.No. 4Randomised evaluation of alternativeelectrosurgical modalities to treatbladder outflow obstruction in menwith benign prostatic hyperplasia.By Fowler C, McAllister W, Plail R,Karim O, Yang Q.No. 5A pragmatic randomised controlledtrial of the cost-effectiveness ofpalliative therapies for patients withinoperable oesophageal cancer.By Shenfine J, McNamee P, Steen N,Bond J, Griffin SM.No. 6Impact of computer-aided detectionprompts on the sensitivity andspecificity of screening mammography.By Taylor P, Champness J, Given-Wilson R, Johnston K, Potts H.No. 7Issues in data monitoring and interimanalysis of trials.By Grant AM, Altman DG, BabikerAB, Campbell MK, Clemens FJ,Darbyshire JH, et al.No. 8Lay public’s understanding of equipoiseand randomisation in randomisedcontrolled trials.By Robinson EJ, Kerr CEP,Stevens AJ, Lilford RJ, Braunholtz DA,Edwards SJ, et al.No. 9Clinical and cost-effectiveness ofelectroconvulsive therapy for depressiveillness, schizophrenia, catatoniaand mania: systematic reviews andeconomic modelling studies.By Greenhalgh J, Knight C, Hind D,Beverley C, Walters S.No. 10Measurement of health-related qualityof life for people with dementia:development of a new instrument(DEMQOL) and an evaluation ofcurrent methodology.By Smith SC, Lamping DL, BanerjeeS, Harwood R, Foley B, Smith P, et al.No. 11Clinical effectiveness and costeffectivenessof drotrecogin alfa(activated) (Xigris ® ) for the treatmentof severe sepsis in adults: a systematicreview and economic evaluation.By Green C, Dinnes J, Takeda A,Shepherd J, Hartwell D, Cave C, et al.No. 12A methodological review of howheterogeneity has been examined insystematic reviews of diagnostic testaccuracy.By Dinnes J, Deeks J, Kirby J,Roderick P.No. 13Cervical screening programmes: canautomation help? Evidence fromsystematic reviews, an economicanalysis and a simulation modellingexercise applied to the UK.By Willis BH, Barton P, Pearmain P,Bryan S, Hyde C.No. 14Laparoscopic surgery for inguinalhernia repair: systematic review ofeffectiveness and economic evaluation.By McCormack K, Wake B, Perez J,Fraser C, Cook J, McIntosh E, et al.No. 15Clinical effectiveness, tolerability andcost-effectiveness of newer drugs forepilepsy in adults: a systematic reviewand economic evaluation.By Wilby J, Kainth A, Hawkins N,Epstein D, McIntosh H, McDaid C, et al.No. 16A randomised controlled trial tocompare the cost-effectiveness oftricyclic antidepressants, selectiveserotonin reuptake inhibitors andlofepramine.By Peveler R, Kendrick T, Buxton M,Longworth L, Baldwin D, Moore M, et al.No. 17Clinical effectiveness and costeffectivenessof immediate angioplastyfor acute myocardial infarction:systematic review and economicevaluation.By Hartwell D, Colquitt J, LovemanE, Clegg AJ, Brodin H, Waugh N, et al.No. 18A randomised controlled comparison ofalternative strategies in stroke care.By Kalra L, Evans A, Perez I,Knapp M, Swift C, Donaldson N.No. 19The investigation and analysis ofcritical incidents and adverse events inhealthcare.By Woloshynowych M, Rogers S,Taylor-Adams S, Vincent C.No. 20Potential use of routine databases inhealth technology assessment.By Raftery J, Roderick P, Stevens A.No. 21Clinical and cost-effectiveness of newerimmunosuppressive regimens in renaltransplantation: a systematic review andmodelling study.By Woodroffe R, Yao GL, Meads C,Bayliss S, Ready A, Raftery J, et al.No. 22A systematic review and economicevaluation of alendronate, etidronate,risedronate, raloxifene and teriparatidefor the prevention and treatment ofpostmenopausal osteoporosis.By Stevenson M, Lloyd Jones M, DeNigris E, Brewer N, Davis S, Oakley J.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 23A systematic review to examinethe impact of psycho-educationalinterventions on health outcomesand costs in adults and children withdifficult asthma.By Smith JR, Mugford M, HollandR, Candy B, Noble MJ, Harrison BDW,et al.No. 24An evaluation of the costs, effectivenessand quality of renal replacementtherapy provision in renal satellite unitsin England and Wales.By Roderick P, Nicholson T, ArmitageA, Mehta R, Mullee M, Gerard K, et al.No. 25Imatinib for the treatment of patientswith unresectable and/or metastaticgastrointestinal stromal tumours:systematic review and economicevaluation.By Wilson J, Connock M, Song F,Yao G, Fry-Smith A, Raftery J, et al.No. 26Indirect comparisons of competinginterventions.By Glenny AM, Altman DG, Song F,Sakarovitch C, Deeks JJ, D’Amico R,et al.No. 27Cost-effectiveness of alternativestrategies for the initial medicalmanagement of non-ST elevation acutecoronary syndrome: systematic reviewand decision-analytical modelling.By Robinson M, Palmer S, SculpherM, Philips Z, Ginnelly L, Bowens A, et al.No. 28Outcomes of electrically stimulatedgracilis neosphincter surgery.By Tillin T, Chambers M, Feldman R.No. 29The effectiveness and cost-effectivenessof pimecrolimus and tacrolimus foratopic eczema: a systematic review andeconomic evaluation.By Garside R, Stein K, CastelnuovoE, Pitt M, Ashcroft D, Dimmock P, et al.No. 30Systematic review on urine albumintesting for early detection of diabeticcomplications.By Newman DJ, Mattock MB,Dawnay ABS, Kerry S, McGuire A,Yaqoob M, et al.No. 31Randomised controlled trial of the costeffectivenessof water-based therapy forlower limb osteoarthritis.By Cochrane T, Davey RC,Matthes Edwards SM.No. 32Longer term clinical and economicbenefits of offering acupuncture care topatients with chronic low back pain.By Thomas KJ, MacPhersonH, Ratcliffe J, Thorpe L, Brazier J,Campbell M, et al.No. 33Cost-effectiveness and safety ofepidural steroids in the managementof sciatica.By Price C, Arden N, Coglan L,Rogers P.No. 34The British Rheumatoid OutcomeStudy Group (BROSG) randomisedcontrolled trial to compare theeffectiveness and cost-effectiveness ofaggressive versus symptomatic therapyin established rheumatoid arthritis.By Symmons D, Tricker K, RobertsC, Davies L, Dawes P, Scott DL.No. 35Conceptual framework and systematicreview of the effects of participants’and professionals’ preferences inrandomised controlled trials.By King M, Nazareth I, Lampe F,Bower P, Chandler M, Morou M, et al.No. 36The clinical and cost-effectiveness ofimplantable cardioverter defibrillators:a systematic review.By Bryant J, Brodin H, Loveman E,Payne E, Clegg A.No. 37A trial of problem-solving bycommunity mental health nurses foranxiety, depression and life difficultiesamong general practice patients. TheCPN-GP study.By Kendrick T, Simons L,Mynors-Wallis L, Gray A, Lathlean J,Pickering R, et al.No. 38The causes and effects of sociodemographicexclusions from clinicaltrials.By Bartlett C, Doyal L, Ebrahim S,Davey P, Bachmann M, Egger M, et al.No. 39Is hydrotherapy cost-effective?A randomised controlled trial ofcombined hydrotherapy programmescompared with physiotherapy landtechniques in children with juvenileidiopathic arthritis.By Epps H, Ginnelly L, Utley M,Southwood T, Gallivan S, Sculpher M,et al.No. 40A randomised controlled trial andcost-effectiveness study of systematicscreening (targeted and totalpopulation screening) versus routinepractice for the detection of atrialfibrillation in people aged 65 and over.The SAFE study.By Hobbs FDR, Fitzmaurice DA,Mant J, Murray E, Jowett S, Bryan S,et al.No. 41Displaced intracapsular hip fracturesin fit, older people: a randomisedcomparison of reduction and fixation,bipolar hemiarthroplasty and total hiparthroplasty.By Keating JF, Grant A, Masson M,Scott NW, Forbes JF.No. 42Long-term outcome of cognitivebehaviour therapy clinical trials incentral Scotland.By Durham RC, Chambers JA,Power KG, Sharp DM, Macdonald RR,Major KA, et al.No. 43The effectiveness and cost-effectivenessof dual-chamber pacemakers comparedwith single-chamber pacemakers forbradycardia due to atrioventricularblock or sick sinus syndrome: systematicreview and economic evaluation.By Castelnuovo E, Stein K, Pitt M,Garside R, Payne E.No. 44Newborn screening for congenital heartdefects: a systematic review and costeffectivenessanalysis.By Knowles R, Griebsch I,Dezateux C, Brown J, Bull C, Wren C.No. 45The clinical and cost-effectiveness ofleft ventricular assist devices for endstageheart failure: a systematic reviewand economic evaluation.By Clegg AJ, Scott DA, Loveman E,Colquitt J, Hutchinson J, Royle P, et al.No. 46The effectiveness of the HeidelbergRetina Tomograph and laser diagnosticglaucoma scanning system (GDx) indetecting and monitoring glaucoma.By Kwartz AJ, Henson DB, HarperRA, Spencer AF, McLeod D.No. 47Clinical and cost-effectiveness ofautologous chondrocyte implantationfor cartilage defects in knee joints:systematic review and economicevaluation.By Clar C, Cummins E, McIntyre L,Thomas S, Lamb J, Bain L, et al.201© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to date202No. 48Systematic review of effectiveness ofdifferent treatments for childhoodretinoblastoma.By McDaid C, Hartley S, BagnallA-M, Ritchie G, Light K, Riemsma R.No. 49Towards evidence-based guidelinesfor the prevention of venousthromboembolism: systematicreviews of mechanical methods, oralanticoagulation, dextran and regionalanaesthesia as thromboprophylaxis.By Roderick P, Ferris G, Wilson K,Halls H, Jackson D, Collins R, et al.No. 50The effectiveness and cost-effectivenessof parent training/educationprogrammes for the treatmentof conduct disorder, includingoppositional defiant disorder, inchildren.By Dretzke J, Frew E, Davenport C,Barlow J, Stewart-Brown S, Sandercock J,et al.Volume 10, 2006No. 1The clinical and cost-effectiveness ofdonepezil, rivastigmine, galantamineand memantine for Alzheimer’sdisease.By Loveman E, Green C, Kirby J,Takeda A, Picot J, Payne E, et al.No. 2FOOD: a multicentre randomised trialevaluating feeding policies in patientsadmitted to hospital with a recentstroke.By Dennis M, Lewis S, Cranswick G,Forbes J.No. 3The clinical effectiveness and costeffectivenessof computed tomographyscreening for lung cancer: systematicreviews.By Black C, Bagust A, Boland A,Walker S, McLeod C, De Verteuil R, et al.No. 4A systematic review of the effectivenessand cost-effectiveness of neuroimagingassessments used to visualise the seizurefocus in people with refractory epilepsybeing considered for surgery.By Whiting P, Gupta R, Burch J,Mujica Mota RE, Wright K, Marson A,et al.No. 5Comparison of conference abstractsand presentations with full-text articlesin the health technology assessments ofrapidly evolving technologies.By Dundar Y, Dodd S, Dickson R,Walley T, Haycox A, Williamson PR.No. 6Systematic review and evaluationof methods of assessing urinaryincontinence.By Martin JL, Williams KS, AbramsKR, Turner DA, Sutton AJ, Chapple C,et al.No. 7The clinical effectiveness and costeffectivenessof newer drugs forchildren with epilepsy. A systematicreview.By Connock M, Frew E, Evans B-W,Bryan S, Cummins C, Fry-Smith A, et al.No. 8Surveillance of Barrett’s oesophagus:exploring the uncertainty throughsystematic review, expert workshop andeconomic modelling.By Garside R, Pitt M, Somerville M,Stein K, Price A, Gilbert N.No. 9Topotecan, pegylated liposomaldoxorubicin hydrochloride andpaclitaxel for second-line or subsequenttreatment of advanced ovarian cancer:a systematic review and economicevaluation.By Main C, Bojke L, Griffin S,Norman G, Barbieri M, Mather L, et al.No. 10Evaluation of molecular techniquesin prediction and diagnosisof cytomegalovirus disease inimmunocompromised patients.By Szczepura A, Westmoreland D,Vinogradova Y, Fox J, Clark M.No. 11Screening for thrombophilia in highrisksituations: systematic reviewand cost-effectiveness analysis. TheThrombosis: Risk and EconomicAssessment of ThrombophiliaScreening (TREATS) study.By Wu O, Robertson L, Twaddle S,Lowe GDO, Clark P, Greaves M, et al.No. 12A series of systematic reviews to informa decision analysis for sampling andtreating infected diabetic foot ulcers.By Nelson EA, O’Meara S, Craig D,Iglesias C, Golder S, Dalton J, et al.No. 13Randomised clinical trial, observationalstudy and assessment of costeffectivenessof the treatment ofvaricose veins (REACTIV trial).By Michaels JA, Campbell WB,Brazier JE, MacIntyre JB, Palfreyman SJ,Ratcliffe J, et al.No. 14The cost-effectiveness of screening fororal cancer in primary care.By Speight PM, Palmer S, Moles DR,Downer MC, Smith DH, Henriksson M,et al.No. 15Measurement of the clinical and costeffectivenessof non-invasive diagnostictesting strategies for deep veinthrombosis.By Goodacre S, Sampson F,Stevenson M, Wailoo A, Sutton A,Thomas S, et al.No. 16Systematic review of the effectivenessand cost-effectiveness of HealOzone ®for the treatment of occlusal pit/fissurecaries and root caries.By Brazzelli M, McKenzie L, FieldingS, Fraser C, Clarkson J, Kilonzo M, et al.No. 17Randomised controlled trials ofconventional antipsychotic versusnew atypical drugs, and new atypicaldrugs versus clozapine, in people withschizophrenia responding poorly to, orintolerant of, current drug treatment.By Lewis SW, Davies L, Jones PB,Barnes TRE, Murray RM, Kerwin R,et al.No. 18Diagnostic tests and algorithms usedin the investigation of haematuria:systematic reviews and economicevaluation.By Rodgers M, Nixon J, Hempel S,Aho T, Kelly J, Neal D, et al.No. 19Cognitive behavioural therapy inaddition to antispasmodic therapy forirritable bowel syndrome in primarycare: randomised controlled trial.By Kennedy TM, Chalder T,McCrone P, Darnley S, Knapp M,Jones RH, et al.No. 20A systematic review of theclinical effectiveness and costeffectivenessof enzyme replacementtherapies for Fabry’s disease andmucopolysaccharidosis type 1.By Connock M, Juarez-Garcia A,Frew E, Mans A, Dretzke J, Fry-Smith A,et al.No. 21Health benefits of antiviral therapy formild chronic hepatitis C: randomisedcontrolled trial and economicevaluation.By Wright M, Grieve R, Roberts J,Main J, Thomas HC, on behalf of theUK Mild Hepatitis C Trial Investigators.No. 22Pressure relieving support surfaces: arandomised evaluation.By Nixon J, Nelson EA, Cranny G,Iglesias CP, Hawkins K, Cullum NA, et al.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 23A systematic review and economicmodel of the effectiveness and costeffectivenessof methylphenidate,dexamfetamine and atomoxetinefor the treatment of attention deficithyperactivity disorder in children andadolescents.By King S, Griffin S, Hodges Z,Weatherly H, Asseburg C, Richardson G,et al.No. 24The clinical effectiveness and costeffectivenessof enzyme replacementtherapy for Gaucher’s disease: asystematic review.By Connock M, Burls A, Frew E,Fry-Smith A, Juarez-Garcia A, McCabe C,et al.No. 25Effectiveness and cost-effectivenessof salicylic acid and cryotherapy forcutaneous warts. An economic decisionmodel.By Thomas KS, Keogh-Brown MR,Chalmers JR, Fordham RJ, Holland RC,Armstrong SJ, et al.No. 26A systematic literature review of theeffectiveness of non-pharmacologicalinterventions to prevent wandering indementia and evaluation of the ethicalimplications and acceptability of theiruse.By Robinson L, Hutchings D, CornerL, Beyer F, Dickinson H, Vanoli A, et al.No. 27A review of the evidence on the effectsand costs of implantable cardioverterdefibrillator therapy in differentpatient groups, and modelling of costeffectivenessand cost–utility for thesegroups in a UK context.By Buxton M, Caine N, Chase D,Connelly D, Grace A, Jackson C, et al.No. 28Adefovir dipivoxil and pegylatedinterferon alfa-2a for the treatment ofchronic hepatitis B: a systematic reviewand economic evaluation.By Shepherd J, Jones J, Takeda A,Davidson P, Price A.No. 29An evaluation of the clinical and costeffectivenessof pulmonary arterycatheters in patient management inintensive care: a systematic review and arandomised controlled trial.By Harvey S, Stevens K, Harrison D,Young D, Brampton W, McCabe C, et al.No. 30Accurate, practical and cost-effectiveassessment of carotid stenosis in theUK.By Wardlaw JM, Chappell FM,Stevenson M, De Nigris E, Thomas S,Gillard J, et al.No. 31Etanercept and infliximab for thetreatment of psoriatic arthritis: asystematic review and economicevaluation.By Woolacott N, Bravo Vergel Y,Hawkins N, Kainth A, Khadjesari Z,Misso K, et al.No. 32The cost-effectiveness of testing forhepatitis C in former injecting drugusers.By Castelnuovo E, Thompson-CoonJ, Pitt M, Cramp M, Siebert U, Price A,et al.No. 33Computerised cognitive behaviourtherapy for depression and anxietyupdate: a systematic review andeconomic evaluation.By Kaltenthaler E, Brazier J,De Nigris E, Tumur I, Ferriter M,Beverley C, et al.No. 34Cost-effectiveness of using prognosticinformation to select women with breastcancer for adjuvant systemic therapy.By Williams C, Brunskill S, Altman D,Briggs A, Campbell H, Clarke M, et al.No. 35Psychological therapies includingdialectical behaviour therapy forborderline personality disorder: asystematic review and preliminaryeconomic evaluation.By Brazier J, Tumur I, Holmes M,Ferriter M, Parry G, Dent-Brown K, et al.No. 36Clinical effectiveness and costeffectivenessof tests for the diagnosisand investigation of urinary tractinfection in children: a systematicreview and economic model.By Whiting P, Westwood M, Bojke L,Palmer S, Richardson G, Cooper J, et al.No. 37Cognitive behavioural therapyin chronic fatigue syndrome: arandomised controlled trial of anoutpatient group programme.By O’Dowd H, Gladwell P, RogersCA, Hollinghurst S, Gregory A.No. 38A comparison of the cost-effectivenessof five strategies for the preventionof nonsteroidal anti-inflammatorydrug-induced gastrointestinal toxicity:a systematic review with economicmodelling.By Brown TJ, Hooper L, Elliott RA,Payne K, Webb R, Roberts C, et al.No. 39The effectiveness and cost-effectivenessof computed tomography screeningfor coronary artery disease: systematicreview.By Waugh N, Black C, Walker S,McIntyre L, Cummins E, Hillis G.No. 40What are the clinical outcome and costeffectivenessof endoscopy undertakenby nurses when compared with doctors?A Multi-Institution Nurse EndoscopyTrial (MINuET).By Williams J, Russell I, Durai D,Cheung W-Y, Farrin A, Bloor K, et al.No. 41The clinical and cost-effectiveness ofoxaliplatin and capecitabine for theadjuvant treatment of colon cancer:systematic review and economicevaluation.By Pandor A, Eggington S, Paisley S,Tappenden P, Sutcliffe P.No. 42A systematic review of the effectivenessof adalimumab, etanercept andinfliximab for the treatment ofrheumatoid arthritis in adults andan economic evaluation of their costeffectiveness.By Chen Y-F, Jobanputra P, Barton P,Jowett S, Bryan S, Clark W, et al.No. 43Telemedicine in dermatology: arandomised controlled trial.By Bowns IR, Collins K, Walters SJ,McDonagh AJG.No. 44Cost-effectiveness of cell salvage andalternative methods of minimisingperioperative allogeneic bloodtransfusion: a systematic review andeconomic model.By Davies L, Brown TJ, Haynes S,Payne K, Elliott RA, McCollum C.No. 45Clinical effectiveness and costeffectivenessof laparoscopic surgeryfor colorectal cancer: systematic reviewsand economic evaluation.By Murray A, Lourenco T, de VerteuilR, Hernandez R, Fraser C, McKinley A,et al.No. 46Etanercept and efalizumab for thetreatment of psoriasis: a systematicreview.By Woolacott N, Hawkins N,Mason A, Kainth A, Khadjesari Z, BravoVergel Y, et al.No. 47Systematic reviews of clinical decisiontools for acute abdominal pain.By Liu JLY, Wyatt JC, Deeks JJ,Clamp S, Keen J, Verde P, et al.No. 48Evaluation of the ventricular assistdevice programme in the UK.By Sharples L, Buxton M, Caine N,Cafferty F, Demiris N, Dyer M, et al.203© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to date204No. 49A systematic review and economicmodel of the clinical and costeffectivenessof immunosuppressivetherapy for renal transplantation inchildren.By Yao G, Albon E, Adi Y, Milford D,Bayliss S, Ready A, et al.No. 50Amniocentesis results: investigation ofanxiety. The ARIA trial.By Hewison J, Nixon J, Fountain J,Cocks K, Jones C, Mason G, et al.Volume 11, 2007No. 1Pemetrexed disodium for the treatmentof malignant pleural mesothelioma:a systematic review and economicevaluation.By Dundar Y, Bagust A, Dickson R,Dodd S, Green J, Haycox A, et al.No. 2A systematic review and economicmodel of the clinical effectivenessand cost-effectiveness of docetaxelin combination with prednisone orprednisolone for the treatment ofhormone-refractory metastatic prostatecancer.By Collins R, Fenwick E, Trowman R,Perard R, Norman G, Light K, et al.No. 3A systematic review of rapid diagnostictests for the detection of tuberculosisinfection.By Dinnes J, Deeks J, Kunst H,Gibson A, Cummins E, Waugh N, et al.No. 4The clinical effectiveness and costeffectivenessof strontium ranelate forthe prevention of osteoporotic fragilityfractures in postmenopausal women.By Stevenson M, Davis S, Lloyd-JonesM, Beverley C.No. 5A systematic review of quantitative andqualitative research on the role andeffectiveness of written informationavailable to patients about individualmedicines.By Raynor DK, BlenkinsoppA, Knapp P, Grime J, Nicolson DJ,Pollock K, et al.No. 6Oral naltrexone as a treatment forrelapse prevention in formerly opioiddependentdrug users: a systematicreview and economic evaluation.By Adi Y, Juarez-Garcia A, Wang D,Jowett S, Frew E, Day E, et al.No. 7Glucocorticoid-induced osteoporosis:a systematic review and cost–utilityanalysis.By Kanis JA, Stevenson M,McCloskey EV, Davis S, Lloyd-Jones M.No. 8Epidemiological, social, diagnostic andeconomic evaluation of populationscreening for genital chlamydialinfection.By Low N, McCarthy A, Macleod J,Salisbury C, Campbell R, Roberts TE,et al.No. 9Methadone and buprenorphine for themanagement of opioid dependence:a systematic review and economicevaluation.By Connock M, Juarez-Garcia A,Jowett S, Frew E, Liu Z, Taylor RJ, et al.No. 10Exercise Evaluation RandomisedTrial (EXERT): a randomised trialcomparing GP referral for leisurecentre-based exercise, community-basedwalking and advice only.By Isaacs AJ, Critchley JA, See TaiS, Buckingham K, Westley D, HarridgeSDR, et al.No. 11Interferon alfa (pegylated and nonpegylated)and ribavirin for thetreatment of mild chronic hepatitisC: a systematic review and economicevaluation.By Shepherd J, Jones J, Hartwell D,Davidson P, Price A, Waugh N.No. 12Systematic review and economicevaluation of bevacizumab andcetuximab for the treatment ofmetastatic colorectal cancer.By Tappenden P, Jones R, Paisley S,Carroll C.No. 13A systematic review and economicevaluation of epoetin alfa, epoetinbeta and darbepoetin alfa in anaemiaassociated with cancer, especially thatattributable to cancer treatment.By Wilson J, Yao GL, Raftery J,Bohlius J, Brunskill S, Sandercock J,et al.No. 14A systematic review and economicevaluation of statins for the preventionof coronary events.By Ward S, Lloyd Jones M, Pandor A,Holmes M, Ara R, Ryan A, et al.No. 15A systematic review of the effectivenessand cost-effectiveness of differentmodels of community-based respitecare for frail older people and theircarers.By Mason A, Weatherly H, SpilsburyK, Arksey H, Golder S, Adamson J, et al.No. 16Additional therapy for youngchildren with spastic cerebral palsy: arandomised controlled trial.By Weindling AM, Cunningham CC,Glenn SM, Edwards RT, Reeves DJ.No. 17Screening for type 2 diabetes: literaturereview and economic modelling.By Waugh N, Scotland G, McNameeP, Gillett M, Brennan A, Goyder E, et al.No. 18The effectiveness and cost-effectivenessof cinacalcet for secondaryhyperparathyroidism in end-stage renaldisease patients on dialysis: a systematicreview and economic evaluation.By Garside R, Pitt M, Anderson R,Mealing S, Roome C, Snaith A, et al.No. 19The clinical effectiveness and costeffectivenessof gemcitabine formetastatic breast cancer: a systematicreview and economic evaluation.By Takeda AL, Jones J, Loveman E,Tan SC, Clegg AJ.No. 20A systematic review of duplexultrasound, magnetic resonanceangiography and computedtomography angiography forthe diagnosis and assessment ofsymptomatic, lower limb peripheralarterial disease.By Collins R, Cranny G, Burch J,Aguiar-Ibáñez R, Craig D, Wright K,et al.No. 21The clinical effectiveness and costeffectivenessof treatments for childrenwith idiopathic steroid-resistantnephrotic syndrome: a systematicreview.By Colquitt JL, Kirby J, Green C,Cooper K, Trompeter RS.No. 22A systematic review of the routinemonitoring of growth in children ofprimary school age to identify growthrelatedconditions.By Fayter D, Nixon J, Hartley S,Rithalia A, Butler G, Rudolf M, et al.No. 23Systematic review of the effectiveness ofpreventing and treating Staphylococcusaureus carriage in reducing peritonealcatheter-related infections.By McCormack K, Rabindranath K,Kilonzo M, Vale L, Fraser C, McIntyre L,et al.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 24The clinical effectiveness and costof repetitive transcranial magneticstimulation versus electroconvulsivetherapy in severe depression: amulticentre pragmatic randomisedcontrolled trial and economic analysis.By McLoughlin DM, Mogg A, ErantiS, Pluck G, Purvis R, Edwards D, et al.No. 25A randomised controlled trial andeconomic evaluation of direct versusindirect and individual versus groupmodes of speech and language therapyfor children with primary languageimpairment.By Boyle J, McCartney E, Forbes J,O’Hare A.No. 26Hormonal therapies for early breastcancer: systematic review and economicevaluation.By Hind D, Ward S, De Nigris E,Simpson E, Carroll C, Wyld L.No. 27Cardioprotection against the toxiceffects of anthracyclines given tochildren with cancer: a systematicreview.By Bryant J, Picot J, Levitt G,Sullivan I, Baxter L, Clegg A.No. 28Adalimumab, etanercept and infliximabfor the treatment of ankylosingspondylitis: a systematic review andeconomic evaluation.By McLeod C, Bagust A, Boland A,Dagenais P, Dickson R, Dundar Y, et al.No. 29Prenatal screening and treatmentstrategies to prevent group Bstreptococcal and other bacterialinfections in early infancy: costeffectivenessand expected value ofinformation analyses.By Colbourn T, Asseburg C, Bojke L,Philips Z, Claxton K, Ades AE, et al.No. 30Clinical effectiveness and costeffectivenessof bone morphogeneticproteins in the non-healing of fracturesand spinal fusion: a systematic review.By Garrison KR, Donell S, Ryder J,Shemilt I, Mugford M, Harvey I, et al.No. 31A randomised controlled trial ofpostoperative radiotherapy followingbreast-conserving surgery in aminimum-risk older population. ThePRIME trial.By Prescott RJ, Kunkler IH, WilliamsLJ, King CC, Jack W, van der Pol M,et al.No. 32Current practice, accuracy, effectivenessand cost-effectiveness of the schoolentry hearing screen.By Bamford J, Fortnum H, BristowK, Smith J, Vamvakas G, Davies L, et al.No. 33The clinical effectiveness and costeffectivenessof inhaled insulin indiabetes mellitus: a systematic reviewand economic evaluation.By Black C, Cummins E, Royle P,Philip S, Waugh N.No. 34Surveillance of cirrhosis forhepatocellular carcinoma: systematicreview and economic analysis.By Thompson Coon J, Rogers G,Hewson P, Wright D, Anderson R,Cramp M, et al.No. 35The Birmingham RehabilitationUptake Maximisation Study (BRUM).Homebased compared with hospitalbasedcardiac rehabilitation in a multiethnicpopulation: cost-effectivenessand patient adherence.By Jolly K, Taylor R, Lip GYH,Greenfield S, Raftery J, Mant J, et al.No. 36A systematic review of the clinical,public health and cost-effectiveness ofrapid diagnostic tests for the detectionand identification of bacterial intestinalpathogens in faeces and food.By Abubakar I, Irvine L, Aldus CF,Wyatt GM, Fordham R, Schelenz S, et al.No. 37A randomised controlled trialexamining the longer-term outcomesof standard versus new antiepilepticdrugs. The SANAD trial.By Marson AG, Appleton R, BakerGA, Chadwick DW, Doughty J, Eaton B,et al.No. 38Clinical effectiveness and costeffectivenessof different modelsof managing long-term oral anticoagulationtherapy: a systematicreview and economic modelling.By Connock M, Stevens C, Fry-SmithA, Jowett S, Fitzmaurice D, Moore D,et al.No. 39A systematic review and economicmodel of the clinical effectivenessand cost-effectiveness of interventionsfor preventing relapse in people withbipolar disorder.By Soares-Weiser K, Bravo Vergel Y,Beynon S, Dunn G, Barbieri M, Duffy S,et al.No. 40Taxanes for the adjuvant treatment ofearly breast cancer: systematic reviewand economic evaluation.By Ward S, Simpson E, Davis S, HindD, Rees A, Wilkinson A.No. 41The clinical effectiveness and costeffectivenessof screening for openangle glaucoma: a systematic reviewand economic evaluation.By Burr JM, Mowatt G, HernándezR, Siddiqui MAR, Cook J, Lourenco T,et al.No. 42Acceptability, benefit and costs of earlyscreening for hearing disability: a studyof potential screening tests and models.By Davis A, Smith P, Ferguson M,Stephens D, Gianopoulos I.No. 43Contamination in trials of educationalinterventions.By Keogh-Brown MR, BachmannMO, Shepstone L, Hewitt C, Howe A,Ramsay CR, et al.No. 44Overview of the clinical effectiveness ofpositron emission tomography imagingin selected cancers.By Facey K, Bradbury I, Laking G,Payne E.No. 45The effectiveness and cost-effectivenessof carmustine implants andtemozolomide for the treatment ofnewly diagnosed high-grade glioma:a systematic review and economicevaluation.By Garside R, Pitt M, Anderson R,Rogers G, Dyer M, Mealing S, et al.No. 46Drug-eluting stents: a systematic reviewand economic evaluation.By Hill RA, Boland A, Dickson R,Dündar Y, Haycox A, McLeod C, et al.No. 47The clinical effectiveness andcost-effectiveness of cardiacresynchronisation (biventricular pacing)for heart failure: systematic review andeconomic model.By Fox M, Mealing S, Anderson R,Dean J, Stein K, Price A, et al.No. 48Recruitment to randomised trials:strategies for trial enrolment andparticipation study. The STEPS study.By Campbell MK, Snowdon C,Francis D, Elbourne D, McDonald AM,Knight R, et al.205© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to dateNo. 49Cost-effectiveness of functionalcardiac testing in the diagnosis andmanagement of coronary arterydisease: a randomised controlled trial.The CECaT trial.By Sharples L, Hughes V, Crean A,Dyer M, Buxton M, Goldsmith K, et al.No. 50Evaluation of diagnostic tests whenthere is no gold standard. A review ofmethods.By Rutjes AWS, ReitsmaJB, Coomarasamy A, Khan KS,Bossuyt PMM.No. 51Systematic reviews of the clinicaleffectiveness and cost-effectiveness ofproton pump inhibitors in acute uppergastrointestinal bleeding.By Leontiadis GI, SreedharanA, Dorward S, Barton P, Delaney B,Howden CW, et al.No. 52A review and critique of modelling inprioritising and designing screeningprogrammes.By Karnon J, Goyder E, TappendenP, McPhie S, Towers I, Brazier J, et al.No. 53An assessment of the impact of theNHS Health Technology AssessmentProgramme.By Hanney S, Buxton M, Green C,Coulson D, Raftery J.Volume 12, 2008No. 1A systematic review and economicmodel of switching fromnonglycopeptide to glycopeptideantibiotic prophylaxis for surgery.By Cranny G, Elliott R, Weatherly H,Chambers D, Hawkins N, Myers L, et al.No. 4Does befriending by trained lay workersimprove psychological well-being andquality of life for carers of peoplewith dementia, and at what cost? Arandomised controlled trial.By Charlesworth G, Shepstone L,Wilson E, Thalanany M, Mugford M,Poland F.No. 5A multi-centre retrospective cohortstudy comparing the efficacy, safetyand cost-effectiveness of hysterectomyand uterine artery embolisation forthe treatment of symptomatic uterinefibroids. The HOPEFUL study.By Hirst A, Dutton S, Wu O, BriggsA, Edwards C, Waldenmaier L, et al.No. 6Methods of prediction and preventionof pre-eclampsia: systematic reviews ofaccuracy and effectiveness literaturewith economic modelling.By Meads CA, Cnossen JS, Meher S,Juarez-Garcia A, ter Riet G, Duley L,et al.No. 7The use of economic evaluations inNHS decision-making: a review andempirical investigation.By Williams I, McIver S, Moore D,Bryan S.No. 8Stapled haemorrhoidectomy(haemorrhoidopexy) for the treatmentof haemorrhoids: a systematic reviewand economic evaluation.By Burch J, Epstein D, Baba-AkbariA, Weatherly H, Fox D, Golder S, et al.No. 9The clinical effectiveness of diabeteseducation models for Type 2 diabetes: asystematic review.By Loveman E, Frampton GK,Clegg AJ.No. 12The clinical effectiveness and costeffectivenessof central venous catheterstreated with anti-infective agents inpreventing bloodstream infections:a systematic review and economicevaluation.By Hockenhull JC, Dwan K, BolandA, Smith G, Bagust A, Dundar Y, et al.No. 13Stepped treatment of older adults onlaxatives. The STOOL trial.By Mihaylov S, Stark C, McColl E,Steen N, Vanoli A, Rubin G, et al.No. 14A randomised controlled trial ofcognitive behaviour therapy inadolescents with major depressiontreated by selective serotonin reuptakeinhibitors. The ADAPT trial.By Goodyer IM, Dubicka B,Wilkinson P, Kelvin R, Roberts C,Byford S, et al.No. 15The use of irinotecan, oxaliplatinand raltitrexed for the treatment ofadvanced colorectal cancer: systematicreview and economic evaluation.By Hind D, Tappenden P, Tumur I,Eggington E, Sutcliffe P, Ryan A.No. 16Ranibizumab and pegaptanib forthe treatment of age-related maculardegeneration: a systematic review andeconomic evaluation.By Colquitt JL, Jones J, Tan SC,Takeda A, Clegg AJ, Price A.No. 17Systematic review of the clinicaleffectiveness and cost-effectivenessof 64-slice or higher computedtomography angiography as analternative to invasive coronaryangiography in the investigation ofcoronary artery disease.By Mowatt G, Cummins E, Waugh N,Walker S, Cook J, Jia X, et al.206No. 2‘Cut down to quit’ with nicotinereplacement therapies in smokingcessation: a systematic review ofeffectiveness and economic analysis.By Wang D, Connock M, Barton P,Fry-Smith A, Aveyard P, Moore D.No. 3A systematic review of the effectivenessof strategies for reducing fracture riskin children with juvenile idiopathicarthritis with additional data on longtermrisk of fracture and cost of diseasemanagement.By Thornton J, Ashcroft D, O’Neill T,Elliott R, Adams J, Roberts C, et al.No. 10Payment to healthcare professionals forpatient recruitment to trials: systematicreview and qualitative study.By Raftery J, Bryant J, Powell J,Kerr C, Hawker S.No. 11Cyclooxygenase-2 selective nonsteroidalanti-inflammatory drugs(etodolac, meloxicam, celecoxib,rofecoxib, etoricoxib, valdecoxib andlumiracoxib) for osteoarthritis andrheumatoid arthritis: a systematicreview and economic evaluation.By Chen Y-F, Jobanputra P, Barton P,Bryan S, Fry-Smith A, Harris G, et al.No. 18Structural neuroimaging in psychosis:a systematic review and economicevaluation.By Albon E, Tsourapas A, Frew E,Davenport C, Oyebode F, Bayliss S, et al.No. 19Systematic review and economicanalysis of the comparativeeffectiveness of different inhaledcorticosteroids and their usage withlong-acting beta 2agonists for thetreatment of chronic asthma in adultsand children aged 12 years and over.By Shepherd J, Rogers G, AndersonR, Main C, Thompson-Coon J,Hartwell D, et al.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 20Systematic review and economicanalysis of the comparativeeffectiveness of different inhaledcorticosteroids and their usage withlong-acting beta 2agonists for thetreatment of chronic asthma in childrenunder the age of 12 years.By Main C, Shepherd J, Anderson R,Rogers G, Thompson-Coon J, Liu Z,et al.No. 21Ezetimibe for the treatment ofhypercholesterolaemia: a systematicreview and economic evaluation.By Ara R, Tumur I, Pandor A,Duenas A, Williams R, Wilkinson A, et al.No. 22Topical or oral ibuprofen for chronicknee pain in older people. The TOIBstudy.By Underwood M, Ashby D, CarnesD, Castelnuovo E, Cross P, Harding G,et al.No. 23A prospective randomised comparisonof minor surgery in primary andsecondary care. The MiSTIC trial.By George S, Pockney P, Primrose J,Smith H, Little P, Kinley H, et al.No. 24A review and critical appraisalof measures of therapist–patientinteractions in mental health settings.By Cahill J, Barkham M, Hardy G,Gilbody S, Richards D, Bower P, et al.No. 25The clinical effectiveness and costeffectivenessof screening programmesfor amblyopia and strabismus inchildren up to the age of 4–5 years:a systematic review and economicevaluation.By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.No. 26A systematic review of the clinicaleffectiveness and cost-effectivenessand economic modelling of minimalincision total hip replacementapproaches in the management ofarthritic disease of the hip.By de Verteuil R, Imamura M, Zhu S,Glazener C, Fraser C, Munro N, et al.No. 27A preliminary model-based assessmentof the cost–utility of a screeningprogramme for early age-relatedmacular degeneration.By Karnon J, Czoski-Murray C,Smith K, Brand C, Chakravarthy U,Davis S, et al.No. 28Intravenous magnesium sulphateand sotalol for prevention of atrialfibrillation after coronary arterybypass surgery: a systematic review andeconomic evaluation.By Shepherd J, Jones J, FramptonGK, Tanajewski L, Turner D, Price A.No. 29Absorbent products for urinary/faecalincontinence: a comparative evaluationof key product categories.By Fader M, Cottenden A, Getliffe K,Gage H, Clarke-O’Neill S, Jamieson K,et al.No. 30A systematic review of repetitivefunctional task practice with modellingof resource use, costs and effectiveness.By French B, Leathley M, Sutton C,McAdam J, Thomas L, Forster A, et al.No. 31The effectiveness and cost-effectivnessof minimal access surgery amongstpeople with gastro-oesophageal refluxdisease – a UK collaborative study. Thereflux trial.By Grant A, Wileman S, Ramsay C,Bojke L, Epstein D, Sculpher M, et al.No. 32Time to full publication of studies ofanti-cancer medicines for breast cancerand the potential for publication bias: ashort systematic review.By Takeda A, Loveman E, Harris P,Hartwell D, Welch K.No. 33Performance of screening tests forchild physical abuse in accident andemergency departments.By Woodman J, Pitt M, Wentz R,Taylor B, Hodes D, Gilbert RE.No. 34Curative catheter ablation in atrialfibrillation and typical atrial flutter:systematic review and economicevaluation.By Rodgers M, McKenna C, PalmerS, Chambers D, Van Hout S, Golder S,et al.No. 35Systematic review and economicmodelling of effectiveness and costutility of surgical treatments for menwith benign prostatic enlargement.By Lourenco T, Armstrong N, N’DowJ, Nabi G, Deverill M, Pickard R, et al.No. 36Immunoprophylaxis against respiratorysyncytial virus (RSV) with palivizumabin children: a systematic review andeconomic evaluation.By Wang D, Cummins C, Bayliss S,Sandercock J, Burls A.Volume 13, 2009No. 1Deferasirox for the treatment of ironoverload associated with regularblood transfusions (transfusionalhaemosiderosis) in patients sufferingwith chronic anaemia: a systematicreview and economic evaluation.By McLeod C, Fleeman N, KirkhamJ, Bagust A, Boland A, Chu P, et al.No. 2Thrombophilia testing in people withvenous thromboembolism: systematicreview and cost-effectiveness analysis.By Simpson EL, Stevenson MD,Rawdin A, Papaioannou D.No. 3Surgical procedures and non-surgicaldevices for the management of nonapnoeicsnoring: a systematic review ofclinical effects and associated treatmentcosts.By Main C, Liu Z, Welch K, WeinerG, Quentin Jones S, Stein K.No. 4Continuous positive airway pressuredevices for the treatment of obstructivesleep apnoea–hypopnoea syndrome: asystematic review and economic analysis.By McDaid C, Griffin S, Weatherly H,Durée K, van der Burgt M, van Hout S,Akers J, et al.No. 5Use of classical and novel biomarkersas prognostic risk factors for localisedprostate cancer: a systematic review.By Sutcliffe P, Hummel S, Simpson E,Young T, Rees A, Wilkinson A, et al.No. 6The harmful health effects ofrecreational ecstasy: a systematic reviewof observational evidence.By Rogers G, Elston J, Garside R,Roome C, Taylor R, Younger P, et al.No. 7Systematic review of the clinicaleffectiveness and cost-effectivenessof oesophageal Doppler monitoringin critically ill and high-risk surgicalpatients.By Mowatt G, Houston G, HernándezR, de Verteuil R, Fraser C, CuthbertsonB, et al.No. 8The use of surrogate outcomes inmodel-based cost-effectiveness analyses:a survey of UK Health TechnologyAssessment reports.By Taylor RS, Elston J.No. 9Controlling Hypertension andHypotension Immediately Post Stroke(CHHIPS) – a randomised controlledtrial.By Potter J, Mistri A, Brodie F,Chernova J, Wilson E, Jagger C, et al.207© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to date208No. 10Routine antenatal anti-D prophylaxisfor RhD-negative women: a systematicreview and economic evaluation.By Pilgrim H, Lloyd-Jones M, Rees A.No. 11Amantadine, oseltamivir and zanamivirfor the prophylaxis of influenza(including a review of existing guidanceno. 67): a systematic review andeconomic evaluation.By Tappenden P, Jackson R, CooperK, Rees A, Simpson E, Read R, et al.No. 12Improving the evaluation oftherapeutic interventions in multiplesclerosis: the role of new psychometricmethods.By Hobart J, Cano S.No. 13Treatment of severe ankle sprain: apragmatic randomised controlled trialcomparing the clinical effectivenessand cost-effectiveness of three types ofmechanical ankle support with tubularbandage. The CAST trial.By Cooke MW, Marsh JL, Clark M,Nakash R, Jarvis RM, Hutton JL, et al.,on behalf of the CAST trial group.No. 14Non-occupational postexposureprophylaxis for HIV: a systematicreview.By Bryant J, Baxter L, Hird S.No. 15Blood glucose self-monitoring in type 2diabetes: a randomised controlled trial.By Farmer AJ, Wade AN, French DP,Simon J, Yudkin P, Gray A, et al.No. 16How far does screening women fordomestic (partner) violence in differenthealth-care settings meet criteria fora screening programme? Systematicreviews of nine UK National ScreeningCommittee criteria.By Feder G, Ramsay J, Dunne D,Rose M, Arsene C, Norman R, et al.No. 17Spinal cord stimulation for chronicpain of neuropathic or ischaemicorigin: systematic review and economicevaluation.By Simpson, EL, Duenas A, HolmesMW, Papaioannou D, Chilcott J.No. 18The role of magnetic resonanceimaging in the identification ofsuspected acoustic neuroma: asystematic review of clinical and costeffectivenessand natural history.By Fortnum H, O’Neill C, Taylor R,Lenthall R, Nikolopoulos T, LightfootG, et al.No. 19Dipsticks and diagnostic algorithms inurinary tract infection: developmentand validation, randomised trial,economic analysis, observational cohortand qualitative study.By Little P, Turner S, Rumsby K,Warner G, Moore M, Lowes JA, et al.No. 20Systematic review of respite care in thefrail elderly.By Shaw C, McNamara R, AbramsK, Cannings-John R, Hood K, LongoM, et al.No. 21Neuroleptics in the treatment ofaggressive challenging behaviour forpeople with intellectual disabilities:a randomised controlled trial(NACHBID).By Tyrer P, Oliver-Africano P, RomeoR, Knapp M, Dickens S, Bouras N, et al.No. 22Randomised controlled trial todetermine the clinical effectivenessand cost-effectiveness of selectiveserotonin reuptake inhibitors plussupportive care, versus supportive carealone, for mild to moderate depressionwith somatic symptoms in primarycare: the THREAD (THREshold forAntiDepressant response) study.By Kendrick T, Chatwin J, Dowrick C,Tylee A, Morriss R, Peveler R, et al.No. 23Diagnostic strategies using DNA testingfor hereditary haemochromatosis inat-risk populations: a systematic reviewand economic evaluation.By Bryant J, Cooper K, Picot J, CleggA, Roderick P, Rosenberg W, et al.No. 24Enhanced external counterpulsationfor the treatment of stable angina andheart failure: a systematic review andeconomic analysis.By McKenna C, McDaid C,Suekarran S, Hawkins N, Claxton K,Light K, et al.No. 25Development of a decision supporttool for primary care management ofpatients with abnormal liver functiontests without clinically apparent liverdisease: a record-linkage populationcohort study and decision analysis(ALFIE).By Donnan PT, McLernon D, DillonJF, Ryder S, Roderick P, Sullivan F, et al.No. 26A systematic review of presumedconsent systems for deceased organdonation.By Rithalia A, McDaid C, SuekarranS, Norman G, Myers L, Sowden A.No. 27Paracetamol and ibuprofen for thetreatment of fever in children: thePITCH randomised controlled trial.By Hay AD, Redmond NM, CostelloeC, Montgomery AA, Fletcher M,Hollinghurst S, et al.No. 28A randomised controlled trial tocompare minimally invasive glucosemonitoring devices with conventionalmonitoring in the management ofinsulin-treated diabetes mellitus(MITRE).By Newman SP, Cooke D, Casbard A,Walker S, Meredith S, Nunn A, et al.No. 29Sensitivity analysis in economicevaluation: an audit of NICE currentpractice and a review of its use andvalue in decision-making.By Andronis L, Barton P, Bryan S.Suppl. 1Trastuzumab for the treatment ofprimary breast cancer in HER2-positivewomen: a single technology appraisal.By Ward S, Pilgrim H, Hind D.Docetaxel for the adjuvant treatmentof early node-positive breast cancer: asingle technology appraisal.By Chilcott J, Lloyd Jones M,Wilkinson A.The use of paclitaxel in themanagement of early stage breastcancer.By Griffin S, Dunn G, Palmer S,Macfarlane K, Brent S, Dyker A, et al.Rituximab for the first-line treatmentof stage III/IV follicular non-Hodgkin’slymphoma.By Dundar Y, Bagust A, Hounsome J,McLeod C, Boland A, Davis H, et al.Bortezomib for the treatment ofmultiple myeloma patients.By Green C, Bryant J, Takeda A,Cooper K, Clegg A, Smith A, et al.Fludarabine phosphate for the firstlinetreatment of chronic lymphocyticleukaemia.By Walker S, Palmer S, Erhorn S,Brent S, Dyker A, Ferrie L, et al.Erlotinib for the treatment of relapsednon-small cell lung cancer.By McLeod C, Bagust A, Boland A,Hockenhull J, Dundar Y, Proudlove C,et al.Cetuximab plus radiotherapy for thetreatment of locally advanced squamouscell carcinoma of the head and neck.By Griffin S, Walker S, Sculpher M,White S, Erhorn S, Brent S, et al.Infliximab for the treatment of adultswith psoriasis.By Loveman E, Turner D, HartwellD, Cooper K, Clegg A.

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48No. 30Psychological interventions forpostnatal depression: clusterrandomised trial and economicevaluation. The PoNDER trial.By Morrell CJ, Warner R, Slade P,Dixon S, Walters S, Paley G, et al.No. 31The effect of different treatmentdurations of clopidogrel in patientswith non-ST-segment elevation acutecoronary syndromes: a systematicreview and value of informationanalysis.By Rogowski R, Burch J, Palmer S,Craigs C, Golder S, Woolacott N.No. 32Systematic review and individualpatient data meta-analysis of diagnosisof heart failure, with modelling ofimplications of different diagnosticstrategies in primary care.By Mant J, Doust J, Roalfe A, BartonP, Cowie MR, Glasziou P, et al.No. 33A multicentre randomised controlledtrial of the use of continuous positiveairway pressure and non-invasivepositive pressure ventilation in the earlytreatment of patients presenting to theemergency department with severeacute cardiogenic pulmonary oedema:the 3CPO trial.By Gray AJ, Goodacre S, NewbyDE, Masson MA, Sampson F, DixonS, et al., on behalf of the 3CPO studyinvestigators.No. 34Early high-dose lipid-lowering therapyto avoid cardiac events: a systematicreview and economic evaluation.By Ara R, Pandor A, Stevens J, ReesA, Rafia R.No. 35Adefovir dipivoxil and pegylatedinterferon alpha for the treatmentof chronic hepatitis B: an updatedsystematic review and economicevaluation.By Jones J, Shepherd J, Baxter L,Gospodarevskaya E, Hartwell D, HarrisP, et al.No. 36Methods to identify postnataldepression in primary care: anintegrated evidence synthesis and valueof information analysis.By Hewitt CE, Gilbody SM, BrealeyS, Paulden M, Palmer S, Mann R, et al.No. 37A double-blind randomised placebocontrolledtrial of topical intranasalcorticosteroids in 4- to 11-year-oldchildren with persistent bilateral otitismedia with effusion in primary care.By Williamson I, Benge S, Barton S,Petrou S, Letley L, Fasey N, et al.No. 38The effectiveness and cost-effectivenessof methods of storing donated kidneysfrom deceased donors: a systematicreview and economic model.By Bond M, Pitt M, Akoh J, MoxhamT, Hoyle M, Anderson R.No. 39Rehabilitation of older patients: dayhospital compared with rehabilitationat home. A randomised controlled trial.By Parker SG, Oliver P, PenningtonM, Bond J, Jagger C, Enderby PM, et al.No. 40Breastfeeding promotion for infants inneonatal units: a systematic review andeconomic analysisBy Renfrew MJ, Craig D, Dyson L,McCormick F, Rice S, King SE, et al.No. 41The clinical effectiveness and costeffectivenessof bariatric (weight loss)surgery for obesity: a systematic review andeconomic evaluation.By Picot J, Jones J, Colquitt JL,Gospodarevskaya E, Loveman E, BaxterL, et al.No. 42Rapid testing for group B streptococcusduring labour: a test accuracy studywith evaluation of acceptability andcost-effectiveness.By Daniels J, Gray J, Pattison H,Roberts T, Edwards E, Milner P, et al.No. 43Screening to prevent spontaneouspreterm birth: systematic reviews ofaccuracy and effectiveness literaturewith economic modelling.By Honest H, Forbes CA, Durée KH,Norman G, Duffy SB, Tsourapas A, et al.No. 44The effectiveness and cost-effectivenessof cochlear implants for severe toprofound deafness in children andadults: a systematic review andeconomic model.By Bond M, Mealing S, Anderson R,Elston J, Weiner G, Taylor RS, et al.Suppl. 2Gemcitabine for the treatment ofmetastatic breast cancer.By Jones J, Takeda A, Tan SC,Cooper K, Loveman E, Clegg A.Varenicline in the management ofsmoking cessation: a single technologyappraisal.By Hind D, Tappenden P, Peters J,Kenjegalieva K.Alteplase for the treatment of acuteischaemic stroke: a single technologyappraisal.By Lloyd Jones M, Holmes M.Rituximab for the treatment ofrheumatoid arthritis.By Bagust A, Boland A, HockenhullJ, Fleeman N, Greenhalgh J, Dundar Y,et al.Omalizumab for the treatment ofsevere persistent allergic asthma.By Jones J, Shepherd J, Hartwell D,Harris P, Cooper K, Takeda A, et al.Rituximab for the treatment of relapsedor refractory stage III or IV follicularnon-Hodgkin’s lymphoma.By Boland A, Bagust A, HockenhullJ, Davis H, Chu P, Dickson R.Adalimumab for the treatment ofpsoriasis.By Turner D, Picot J, Cooper K,Loveman E.Dabigatran etexilate for the preventionof venous thromboembolism in patientsundergoing elective hip and kneesurgery: a single technology appraisal.By Holmes M, C Carroll C,Papaioannou D.Romiplostim for the treatmentof chronic immune or idiopathicthrombocytopenic purpura: a singletechnology appraisal.By Mowatt G, Boachie C, CrowtherM, Fraser C, Hernández R, Jia X, et al.Sunitinib for the treatment ofgastrointestinal stromal tumours: acritique of the submission from Pfizer.By Bond M, Hoyle M, Moxham T,Napier M, Anderson R.No. 45Vitamin K to prevent fractures inolder women: systematic review andeconomic evaluation.By Stevenson M, Lloyd-Jones M,Papaioannou D.No. 46The effects of biofeedback for thetreatment of essential hypertension: asystematic review.By Greenhalgh J, Dickson R,Dundar Y.No. 47A randomised controlled trial of theuse of aciclovir and/or prednisolone forthe early treatment of Bell’s palsy: theBELLS study.By Sullivan FM, Swan IRC, DonnanPT, Morrison JM, Smith BH, McKinstryB, et al.Suppl. 3Lapatinib for the treatment of HER2-overexpressing breast cancer.By Jones J, Takeda A, Picot J, vonKeyserlingk C, Clegg A.Infliximab for the treatment ofulcerative colitis.By Hyde C, Bryan S, Juarez-Garcia A,Andronis L, Fry-Smith A.209© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment reports published to dateRimonabant for the treatment ofoverweight and obese people.By Burch J, McKenna C, Palmer S,Norman G, Glanville J, Sculpher M, etal.Telbivudine for the treatment ofchronic hepatitis B infection.By Hartwell D, Jones J, Harris P,Cooper K.Entecavir for the treatment of chronichepatitis B infection.By Shepherd J, Gospodarevskaya E,Frampton G, Cooper, K.Febuxostat for the treatment ofhyperuricaemia in people with gout: asingle technology appraisal.By Stevenson M, Pandor A.Rivaroxaban for the prevention ofvenous thromboembolism: a singletechnology appraisal.By Stevenson M, Scope A, Holmes M,Rees A, Kaltenthaler E.Cetuximab for the treatment ofrecurrent and/or metastatic squamouscell carcinoma of the head and neck.By Greenhalgh J, Bagust A, BolandA, Fleeman N, McLeod C, Dundar Y,et al.Mifamurtide for the treatment ofosteosarcoma: a single technologyappraisal.By Pandor A, Fitzgerald P, StevensonM, Papaioannou D.Ustekinumab for the treatment ofmoderate to severe psoriasis.By Gospodarevskaya E, Picot J,Cooper K, Loveman E, Takeda A.210

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48Health Technology AssessmentprogrammeDirector,Professor Tom Walley,Director, NIHR HTAprogramme, Professor ofClinical Pharmacology,University of LiverpoolDeputy Director,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of SheffieldMembersPrioritisation Strategy GroupChair,Professor Tom Walley,Director, NIHR HTAprogramme, Professor ofClinical Pharmacology,University of LiverpoolDeputy Chair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of SheffieldDr Bob Coates,Consultant Advisor, NETSCC,HTADr Andrew Cook,Consultant Advisor, NETSCC,HTADr Peter Davidson,Director of Science Support,NETSCC, HTAProfessor Robin E Ferner,Consultant Physician andDirector, West Midlands Centrefor Adverse Drug Reactions,City Hospital NHS Trust,BirminghamProfessor Paul Glasziou,Professor of Evidence-BasedMedicine, University of OxfordDr Nick Hicks,Director of NHS Support,NETSCC, HTADr Edmund Jessop,Medical Adviser, NationalSpecialist, NationalCommissioning Group (NCG),Department of Health, LondonMs Lynn Kerridge,Chief Executive Officer,NETSCC and NETSCC, HTADr Ruairidh Milne,Director of Strategy andDevelopment, NETSCCMs Kay Pattison,Section Head, NHS R&DProgramme, Department ofHealthMs Pamela Young,Specialist Programme Manager,NETSCC, HTAMembersProgramme Director,Professor Tom Walley,Director, NIHR HTAprogramme, Professor ofClinical Pharmacology,University of LiverpoolChair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of SheffieldDeputy Chair,Dr Andrew Farmer,Senior Lecturer in GeneralPractice, Department ofPrimary Health Care,University of OxfordProfessor Ann Ashburn,Professor of Rehabilitationand Head of Research,Southampton General HospitalObserversHTA Commissioning BoardProfessor Deborah Ashby,Professor of Medical Statistics,Queen Mary, University ofLondonProfessor John Cairns,Professor of Health Economics,London School of Hygiene andTropical MedicineProfessor Peter Croft,Director of Primary CareSciences Research Centre, KeeleUniversityProfessor Nicky Cullum,Director of Centre for Evidence-Based Nursing, University ofYorkProfessor Jenny Donovan,Professor of Social Medicine,University of BristolProfessor Steve Halligan,Professor of GastrointestinalRadiology, University CollegeHospital, LondonProfessor Freddie Hamdy,Professor of Urology,University of SheffieldProfessor Allan House,Professor of Liaison Psychiatry,University of LeedsDr Martin J Landray,Reader in Epidemiology,Honorary Consultant Physician,Clinical Trial Service Unit,University of OxfordProfessor Stuart Logan,Director of Health & SocialCare Research, The PeninsulaMedical School, Universities ofExeter and PlymouthDr Rafael Perera,Lecturer in Medical Statisitics,Department of Primary HealthCare, Univeristy of OxfordProfessor Ian Roberts,.Professor of Epidemiology &Public Health, London Schoolof Hygiene and TropicalMedicineProfessor Mark Sculpher,Professor of Health Economics,University of YorkProfessor Helen Smith,Professor of Primary Care,University of BrightonProfessor Kate Thomas,Professor of Complementary &Alternative Medicine Research,University of LeedsProfessor David JohnTorgerson,Director of York Trials Unit,University of YorkProfessor Hywel Williams,Professor of Dermato-Epidemiology, University ofNottinghamMs Kay Pattison,Section Head, NHS R&DProgramme, Department ofHealthDr Morven Roberts,Clinical Trials Manager,Medical Research Council211© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment programmeMembersDiagnostic Technologies & Screening PanelChair,Professor Paul Glasziou,Professor of Evidence-BasedMedicine, University of OxfordDeputy Chair,Dr David Elliman,Consultant Paediatrician andHonorary Senior Lecturer,Great Ormond Street Hospital,LondonProfessor Judith E Adams,Consultant Radiologist,Manchester Royal Infirmary,Central Manchester &Manchester Children’sUniversity Hospitals NHS Trust,and Professor of DiagnosticRadiology, Imaging Scienceand Biomedical Engineering,Cancer & Imaging Sciences,University of ManchesterMs Jane Bates,Consultant UltrasoundPractitioner, UltrasoundDepartment, Leeds TeachingHospital NHS TrustDr Stephanie Dancer,Consultant Microbiologist,Hairmyres Hospital, EastKilbrideProfessor Glyn Elwyn,Primary Medical Care ResearchGroup, Swansea Clinical School,University of WalesDr Ron Gray,Consultant ClinicalEpidemiologist, Departmentof Public Health, University ofOxfordProfessor Paul D Griffiths,Professor of Radiology,University of SheffieldDr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist, NationalPerinatal Epidemiology Unit,OxfordDr Susanne M Ludgate,Medical Director, Medicines &Healthcare Products RegulatoryAgency, LondonDr Anne Mackie,Director of Programmes, UKNational Screening CommitteeDr Michael Millar,Consultant Senior Lecturer inMicrobiology, Barts and TheLondon NHS Trust, RoyalLondon HospitalMr Stephen Pilling,Director, Centre for Outcomes,Research & Effectiveness,Joint Director, NationalCollaborating Centre forMental Health, UniversityCollege LondonMrs Una Rennard,Service User RepresentativeDr Phil Shackley,Senior Lecturer in HealthEconomics, School ofPopulation and HealthSciences, University ofNewcastle upon TyneDr W Stuart A Smellie,Consultant in ChemicalPathology, Bishop AucklandGeneral HospitalDr Nicholas Summerton,Consultant Clinical and PublicHealth Advisor, NICEMs Dawn Talbot,Service User RepresentativeDr Graham Taylor,Scientific Advisor, RegionalDNA Laboratory, St James’sUniversity Hospital, LeedsProfessor Lindsay WilsonTurnbull,Scientific Director of theCentre for Magnetic ResonanceInvestigations and YCRProfessor of Radiology, HullRoyal InfirmaryObserversDr Tim Elliott,Team Leader, CancerScreening, Department ofHealthDr Catherine Moody,Programme Manager,Neuroscience and MentalHealth BoardDr Ursula Wells,Principal Research Officer,Department of HealthMembersPharmaceuticals PanelChair,Professor Robin Ferner,Consultant Physician andDirector, West Midlands Centrefor Adverse Drug Reactions,City Hospital NHS Trust,BirminghamDeputy Chair,Professor Imti Choonara,Professor in Child Health,University of NottinghamMrs Nicola Carey,Senior Research Fellow, .School of Health and SocialCare, The University ofReadingMr John Chapman,Service User RepresentativeObserversDr Peter Elton,Director of Public Health,Bury Primary Care TrustDr Ben Goldacre,Research Fellow, Division ofPsychological Medicine andPsychiatry, King’s CollegeLondonMrs Barbara Greggains,Service User RepresentativeDr Bill Gutteridge,Medical Adviser, LondonStrategic Health AuthorityDr Dyfrig Hughes,Reader in Pharmacoeconomicsand Deputy Director, Centrefor Economics and Policy inHealth, IMSCaR, BangorUniversityProfessor Jonathan Ledermann,Professor of Medical Oncologyand Director of the CancerResearch UK and UniversityCollege London Cancer TrialsCentreDr Yoon K Loke,Senior Lecturer in ClinicalPharmacology, University ofEast AngliaProfessor Femi Oyebode,Consultant Psychiatristand Head of Department,University of BirminghamDr Andrew Prentice,Senior Lecturer and ConsultantObstetrician and Gynaecologist,The Rosie Hospital, Universityof CambridgeDr Martin Shelly,General Practitioner, Leeds,and Associate Director, NHSClinical Governance SupportTeam, LeicesterDr Gillian Shepherd,Director, Health and ClinicalExcellence, Merck Serono LtdMrs Katrina Simister,Assistant Director NewMedicines, National PrescribingCentre, LiverpoolMr David Symes,Service User RepresentativeDr Lesley Wise,Unit Manager,PharmacoepidemiologyResearch Unit, VRMM,Medicines & HealthcareProducts Regulatory Agency212Ms Kay Pattison,Section Head, NHS R&DProgramme, Department ofHealthMr Simon Reeve,Head of Clinical and Cost-Effectiveness, Medicines,Pharmacy and Industry Group,Department of HealthDr Heike Weber,Programme Manager,Medical Research CouncilDr Ursula Wells,Principal Research Officer,Department of HealthCurrent and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk)

DOI: 10.3310/hta13480 Health Technology Assessment 2009; Vol. 13: No. 48MembersTherapeutic Procedures PanelChair,Dr John C Pounsford,Consultant Physician, NorthBristol NHS TrustDeputy Chair,Professor Scott Weich,Professor of Psychiatry, Divisionof Health in the Community,University of Warwick,CoventryProfessor Jane Barlow,Professor of Public Health inthe Early Years, Health SciencesResearch Institute, WarwickMedical School, CoventryMs Maree Barnett,Acting Branch Head of VascularProgramme, Department ofHealthMrs Val Carlill,Service User RepresentativeMrs Anthea De Barton-Watson,Service User RepresentativeMr Mark Emberton,Senior Lecturer in OncologicalUrology, Institute of Urology,University College Hospital,LondonProfessor Steve Goodacre,Professor of EmergencyMedicine, University ofSheffieldProfessor Christopher Griffiths,Professor of Primary Care, Bartsand The London School ofMedicine and DentistryMr Paul Hilton,Consultant Gynaecologistand Urogynaecologist, RoyalVictoria Infirmary, Newcastleupon TyneProfessor Nicholas James,Professor of Clinical Oncology,University of Birmingham,and Consultant in ClinicalOncology, Queen ElizabethHospitalDr Peter Martin,Consultant Neurologist,Addenbrooke’s Hospital,CambridgeDr Kate Radford,Senior Lecturer (Research),Clinical Practice ResearchUnit, University of CentralLancashire, PrestonMr Jim ReeceService User RepresentativeDr Karen Roberts,Nurse Consultant, Dunston HillHospital CottagesObserversDr Phillip Leech,Principal Medical Officer forPrimary Care, Department ofHealthMs Kay Pattison,Section Head, NHS R&DProgramme, Department ofHealthMembersChair,Dr Edmund Jessop,Medical Adviser, NationalSpecialist, NationalCommissioning Group (NCG),LondonDeputy Chair,Dr David Pencheon,Director, NHS SustainableDevelopment Unit, CambridgeDr Elizabeth Fellow-Smith,Medical Director, West LondonMental Health Trust, MiddlesexDr Morven Roberts,Clinical Trials Manager,Medical Research CouncilProfessor Tom Walley,Director, NIHR HTAprogramme, Professor ofClinical Pharmacology,University of LiverpoolDisease Prevention PanelDr John Jackson,General Practitioner, ParkwayMedical Centre, Newcastleupon TyneProfessor Mike Kelly,Director, Centre for PublicHealth Excellence, NICE,LondonDr Chris McCall,General Practitioner, TheHadleigh Practice, CorfeMullen, DorsetMs Jeanett Martin,Director of Nursing, BarnDocLimited, Lewisham PrimaryCare TrustDr Julie Mytton,Locum Consultant in PublicHealth Medicine, BristolPrimary Care TrustMiss Nicky Mullany,Service User RepresentativeProfessor Ian Roberts,Professor of Epidemiology andPublic Health, London Schoolof Hygiene & Tropical MedicineProfessor Ken Stein,Senior Clinical Lecturer inPublic Health, University ofExeterDr Ursula Wells,Principal Research Officer,Department of HealthDr Kieran Sweeney,Honorary Clinical SeniorLecturer, Peninsula Collegeof Medicine and Dentistry,Universities of Exeter andPlymouthProfessor Carol Tannahill,Glasgow Centre for PopulationHealthProfessor Margaret Thorogood,Professor of Epidemiology,University of Warwick MedicalSchool, CoventryObserversMs Christine McGuire,Research & Development,Department of HealthDr Caroline Stone,Programme Manager, MedicalResearch Council213© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Health Technology Assessment programmeMembersExpert Advisory Network214Professor Douglas Altman,Professor of Statistics inMedicine, Centre for Statisticsin Medicine, University ofOxfordProfessor John Bond,Professor of Social Gerontology& Health Services Research,University of Newcastle uponTyneProfessor Andrew Bradbury,Professor of Vascular Surgery,Solihull Hospital, BirminghamMr Shaun Brogan,Chief Executive, RidgewayPrimary Care Group, AylesburyMrs Stella Burnside OBE,Chief Executive, Regulationand Improvement Authority,BelfastMs Tracy Bury,Project Manager, WorldConfederation for PhysicalTherapy, LondonProfessor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine, Universityof SouthamptonDr Christine Clark,Medical Writer and ConsultantPharmacist, RossendaleProfessor Collette Clifford,Professor of Nursing andHead of Research, TheMedical School, University ofBirminghamProfessor Barry Cookson,Director, Laboratory of HospitalInfection, Public HealthLaboratory Service, LondonDr Carl Counsell,Clinical Senior Lecturer inNeurology, University ofAberdeenProfessor Howard Cuckle,Professor of ReproductiveEpidemiology, Departmentof Paediatrics, Obstetrics &Gynaecology, University ofLeedsDr Katherine Darton,Information Unit, MIND – TheMental Health Charity, LondonProfessor Carol Dezateux,Professor of PaediatricEpidemiology, Institute of ChildHealth, LondonMr John Dunning,Consultant CardiothoracicSurgeon, Papworth HospitalNHS Trust, CambridgeMr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,GloucesterProfessor Martin Eccles,Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon TyneProfessor Pam Enderby,Dean of Faculty of Medicine,Institute of General Practiceand Primary Care, University ofSheffieldProfessor Gene Feder,Professor of Primary CareResearch & Development,Centre for Health Sciences,Barts and The London Schoolof Medicine and DentistryMr Leonard R Fenwick,Chief Executive, FreemanHospital, Newcastle upon TyneMrs Gillian Fletcher,Antenatal Teacher and Tutorand President, NationalChildbirth Trust, HenfieldProfessor Jayne Franklyn,Professor of Medicine,University of BirminghamMr Tam Fry,Honorary Chairman, ChildGrowth Foundation, LondonProfessor Fiona Gilbert,Consultant Radiologist andNCRN Member, University ofAberdeenProfessor Paul Gregg,Professor of OrthopaedicSurgical Science, South TeesHospital NHS TrustBec Hanley,Co-director, TwoCan Associates,West SussexDr Maryann L Hardy,Senior Lecturer, University ofBradfordMrs Sharon Hart,Healthcare ManagementConsultant, ReadingProfessor Robert E Hawkins,CRC Professor and Directorof Medical Oncology, ChristieCRC Research Centre,Christie Hospital NHS Trust,ManchesterProfessor Richard Hobbs,Head of Department of PrimaryCare & General Practice,University of BirminghamProfessor Alan Horwich,Dean and Section Chairman,The Institute of CancerResearch, LondonProfessor Allen Hutchinson,Director of Public Health andDeputy Dean of ScHARR,University of SheffieldProfessor Peter Jones,Professor of Psychiatry,University of Cambridge,CambridgeProfessor Stan Kaye,Cancer Research UK Professorof Medical Oncology, RoyalMarsden Hospital and Instituteof Cancer Research, SurreyDr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,ThameDr Donna Lamping,Research Degrees ProgrammeDirector and Reader inPsychology, Health ServicesResearch Unit, London Schoolof Hygiene and TropicalMedicine, LondonMr George Levvy,Chief Executive, MotorNeurone Disease Association,NorthamptonProfessor James Lindesay,Professor of Psychiatry for theElderly, University of LeicesterProfessor Julian Little,Professor of Human GenomeEpidemiology, University ofOttawaProfessor Alistaire McGuire,Professor of Health Economics,London School of EconomicsProfessor Rajan Madhok,Medical Director and Directorof Public Health, Directorateof Clinical Strategy & PublicHealth, North & East Yorkshire& Northern LincolnshireHealth Authority, YorkProfessor Alexander Markham,Director, Molecular MedicineUnit, St James’s UniversityHospital, LeedsDr Peter Moore,Freelance Science Writer,AshteadDr Andrew Mortimore,Public Health Director,Southampton City PrimaryCare TrustDr Sue Moss,Associate Director, CancerScreening Evaluation Unit,Institute of Cancer Research,SuttonProfessor Miranda Mugford,Professor of Health Economicsand Group Co-ordinator,University of East AngliaProfessor Jim Neilson,Head of School of Reproductive& Developmental Medicineand Professor of Obstetricsand Gynaecology, University ofLiverpoolMrs Julietta Patnick,National Co-ordinator, NHSCancer Screening Programmes,SheffieldProfessor Robert Peveler,Professor of Liaison Psychiatry,Royal South Hants Hospital,SouthamptonProfessor Chris Price,Director of Clinical Research,Bayer Diagnostics Europe,Stoke PogesProfessor William Rosenberg,Professor of Hepatologyand Consultant Physician,University of SouthamptonProfessor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburghDr Susan Schonfield,Consultant in Public Health,Hillingdon Primary Care Trust,MiddlesexDr Eamonn Sheridan,Consultant in Clinical Genetics,St James’s University Hospital,LeedsDr Margaret Somerville,Director of Public HealthLearning, Peninsula MedicalSchool, University of PlymouthProfessor Sarah Stewart-Brown,Professor of Public Health,Division of Health in theCommunity, University ofWarwick, CoventryProfessor Ala Szczepura,Professor of Health ServiceResearch, Centre for HealthServices Studies, University ofWarwick, CoventryMrs Joan Webster,Consumer Member, SouthernDerbyshire Community HealthCouncilProfessor Martin Whittle,Clinical Co-director, NationalCo-ordinating Centre forWomen’s and Children’sHealth, LymingtonCurrent and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk)

This version of the monograph does not include some of the appendices. This is to savedownload time from the HTA website.The printed version also excludes some of the the appendices.View/download the appendices

FeedbackThe HTA programme and the authors would like to knowyour views about this report.The Correspondence Page on the HTA website(www.hta.ac.uk) is a convenient way to publishyour comments. If you prefer, you can send your commentsto the address below, telling us whether you would likeus to transfer them to the website.We look forward to hearing from you.NETSCC, Health Technology AssessmentAlpha HouseUniversity of Southampton Science ParkSouthampton SO16 7NS, UKEmail: hta@hta.ac.ukwww.hta.ac.uk ISSN 1366-5278